Selective nr2b antagonists

ABSTRACT

The disclosure generally relates to compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands of the NR2B receptor and may be useful for the treatment of various disorders of the central nervous system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Continuation application claims the benefit of U.S. Ser. No.16/225,850 filed Dec. 19, 2018, now pending, which in turn is acontinuation application which claims the benefit of U.S. Ser. No.15/971,067 filed May 4, 2018, now abandoned, which in turn is aContinuation application which claims the benefit of U.S. Ser. No.15/846,672 filed Dec. 19, 2017, now abandoned, which in turn is aContinuation application which claims the benefit of U.S. Ser. No.15/706,172 filed Sep. 15, 2017, now abandoned, which in turn is aContinuation application which claims the benefit of U.S. Ser. No.15/604,904 filed May 25, 2017, now abandoned, which in turn is aContinuation application claims the benefit of U.S. Ser. No. 14/882,041filed Oct. 13, 2015, now abandoned, which in turn is a Continuationapplication which claims the benefit of U.S. Ser. No. 14/589,205 filedJan. 5, 2015, now U.S. Pat. No. 9,221,796, which in turn is aNon-Provisional application which claims the benefit of Provisionalapplication U.S. Ser. No. 61/925,363 filed Jan. 9, 2014, now expired,hereby incorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

The disclosure generally relates to compounds of formula I, includingtheir salts, as well as compositions and methods of using the compounds.The compounds are ligands for the NR2B NMDA receptor and may be usefulfor the treatment of various disorders of the central nervous system.

N-Methyl-D-aspartate (NMDA) receptors are ion channels which are gatedby the binding of glutamate, an excitatory neurotransmitter in thecentral nervous system. They are thought to play a key role in thedevelopment of a number of neurological diseases, including depression,neuropathic pain, Alzheimer's disease, and Parkinson's disease.Functional NMDA receptors are tetrameric structures primarily composedof two NR1 and two NR2 subunits. The NR2 subunit is further subdividedinto four individual subtypes: NR2A, NR2B, NR2C, and NR2D, which aredifferentially distributed throughout the brain. Antagonists orallosteric modulators of NMDA receptors, in particular NR2Bsubunit-containing channels, have been investigated as therapeuticagents for the treatment of major depressive disorder (G. Sanacora,2008, Nature Rev. Drug Disc. 7: 426-437).

The NR2B receptor contains additional ligand binding sites in additionto that for glutamate. Non-selective NMDA antagonists such as Ketamineare pore blockers, interfering with the transport of Ca⁺⁺ through thechannel. Ketamine has demonstrated rapid and enduring antidepressantproperties in human clinical trials as an i.v. drug. Additionally,efficacy was maintained with repeated, intermittent infusions ofKetamine (Zarate et al., 2006, Arch. Gen. Psychiatry 63: 856-864). Thisclass of drugs, though, has limited therapeutic value because of its CNSside effects, including dissociative effects.

An allosteric, non-competitive binding site has also been identified inthe N-terminal domain of NR2B. Agents which bind selectively at thissite, such as Traxoprodil, exhibited a sustained antidepressant responseand improved side effect profile in human clinical trials as an i.v.drug (Preskorn et al., 2008, J. Clin. Psychopharmacol., 28: 631-637, andF. S. Menniti, et al., 1998, CNS Drug Reviews, 4, 4, 307-322). However,development of drugs from this class has been hindered by lowbioavailability, poor pharmacokinetics, and lack of selectivity againstother pharmacological targets including the hERG ion channel. Blockadeof the hERG ion channel can lead to cardiac arrhythmias, including thepotentially fatal Torsades de pointe, thus selectivity against thischannel is critical. Thus, in the treatment of major depressivedisorder, there remains an unmet clinical need for the development ofeffective NR2B-selective negative allosteric modulators which have afavorable tolerability profile.

NR2B receptor antagonists have been disclosed in PCT publication WO2009/006437.

The invention provides technical advantages, for example, the compoundsare novel and are ligands for the NR2B receptor and may be useful forthe treatment of various disorders of the central nervous system.Additionally, the compounds provide advantages for pharmaceutical uses,for example, with regard to one or more of their mechanism of action,binding, inhibition efficacy, target selectivity, solubility, safetyprofiles, or bioavailability.

DESCRIPTION OF THE INVENTION

The invention encompasses compounds of Formula I, includingpharmaceutically acceptable salts, pharmaceutical compositions, andtheir use in treating disorders related to levels of tachykinins orserotonin or both.

One aspect of the invention is a compound of formula I

where:Ar¹ is phenyl or indanyl and is substituted with 0-3 substituentsselected from cyano, halo, alkyl, haloalkyl, and haloalkoxy;Ar² is phenyl substituted with 1 OH substituent and also substitutedwith 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, andhaloalkoxy;X is a bond or C₁-C₃ alkylene;n is 1 or 2; andring A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,homopiperidinyl, or homopiperazinyl and is substituted with 0-4substituents selected from halo, alkyl, hydroxy, or alkoxy; or apharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where n is 1and ring A is piperidinyl substituted with 0-2 halo substituents.

Another aspect of the invention is a compound of formula I where Ar¹ isphenyl substituted with 0-3 substituents selected from cyano, halo,alkyl, haloalkyl, and haloalkoxy.

Another aspect of the invention is a compound of formula I where Ar² isp-hydroxyphenyl.

Another aspect of the invention is a compound of formula I where X ismethylene.

Another aspect of the invention is the compound of formula I:(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-oneor a pharmaceutically acceptable salt thereof

For a compound of formula I, the scope of any instance of a variablesubstituent, including Ar¹, Ar², Ar³ X, and n can be used independentlywith the scope of any other instance of a variable substituent. As such,the invention includes combinations of the different aspects.

Unless specified otherwise, these terms have the following meanings.“Alkyl” means a straight or branched alkyl group composed of 1 to 6carbons. “Alkenyl” means a straight or branched alkyl group composed of2 to 6 carbons with at least one double bond. “Alkynyl” means a straightor branched alkyl group composed of 2 to 6 carbons with at least onetriple bond. “Cycloalkyl” means a monocyclic ring system composed of 3to 7 carbons. Terms with a hydrocarbon moiety (e.g. alkoxy) includestraight and branched isomers for the hydrocarbon portion. “Halo”includes fluoro, chloro, bromo, and iodo. “Haloalkyl” and “haloalkoxy”include all halogenated isomers from monohalo to perhalo. “Aryl” means amonocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbonatoms, or a bicyclic fused ring system wherein one or both of the ringsis a phenyl group. Bicyclic fused ring systems consist of a phenyl groupfused to a four- to six-membered aromatic or non-aromatic carbocyclicring. Representative examples of aryl groups include, but are notlimited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.“Heteroaryl” means a 5 to 7 membered monocyclic or 8 to 11 memberedbicyclic aromatic ring system with 1-5 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur. Parenthetic andmultiparenthetic terms are intended to clarify bonding relationships tothose skilled in the art. For example, a term such as ((R)alkyl) meansan alkyl substituent further substituted with the substituent R.

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

Some Formula I compounds contain at least one asymmetric carbon atom, anexample of which is shown below. The invention includes allstereoisomeric forms of the compounds, both mixtures and separatedisomers. Mixtures of stereoisomers can be separated into individualisomers by methods known in the art. The compounds include alltautomeric forms.

The invention is intended to include all isotopes of atoms occurring inthe present compounds. Isotopes include those atoms having the sameatomic number but different mass numbers. By way of general example andwithout limitation, isotopes of hydrogen include deuterium and tritium.Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeled compoundsof the invention can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed herein, using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent otherwise employed. Such compounds mayhave a variety of potential uses, for example as standards and reagentsin determining biological activity. In the case of stable isotopes, suchcompounds may have the potential to favorably modify biological,pharmacological, or pharmacokinetic properties.

Synthetic Methods

Compounds of Formula I may be made by methods known in the art includingthose described below and including variations within the skill of theart. Some reagents and intermediates are known in the art. Otherreagents and intermediates can be made by methods known in the art usingreadily available materials. The variables (e.g. numbered “R”substituents) used to describe the synthesis of the compounds areintended only to illustrate how to make the compounds and are not to beconfused with variables used in the claims or in other sections of thespecification. The following methods are for illustrative purposes andare not intended to limit the scope of the invention. The schemesencompass reasonable variations known in the art.

Synthesis of the desired compounds I may begin with the condensation ofanilines/benzyl amines I with α, ω-dibromoalkanoyl chlorides III toyield amides/anilides IV, which may be cyclized to1-phenyl/benzyl-3-bromo-pyrrolidinones/piperidinones V, as shown insynthetic scheme 1.

The 1-phenyl/benzyl-3-bromo-pyrrolidinones/piperidinones V may bereacted with (4-oxy-phenyl)cyclic amines VI in the presence of base toproduce protected products VII, which may be subjected to cleavageconditions appropriate for the protecting group (PG₁) to generate finalproducts I, which may be separated into individualenantiomers/diastereomers I*, as shown in synthetic scheme 2.

Compounds Ia may be prepared by condensing1-phenyl/benzyl-3-bromo-pyrrolidinones/piperidinones V with substituted4(4-oxyphenyl)piperidines VIIIa-c to generate protected intermediatesIX, which may be subjected to cleavage conditions appropriate for theprotecting group (PG₁) to generate final products Ia, which may beseparated into individual enantiomers/diastereomers Ia*, as shown insynthetic scheme 3.

The 4(4-oxyphenyl)piperidines VIIIa-c may be synthesized in turn by asequence starting with a protected tetrahydropiperidine X, which can behydroxylated via hydroboration/oxidation to give the protectedhydroxypiperidine XI, which may be either directly transformed into theprotected fluoropiperidine XII by treatment with DAST or oxidized intothe protected 3-oxopiperidine XIII, which may be further transformedinto protected 3,3-difluoropiperidines XIV via treatment with DAST. XI,XII, and XIV may be transformed into VIIIa, VIIIb, and VIIIc,respectively, by employing cleaving conditions appropriate for theprotecting group (PG₂), as shown in synthetic scheme 3a.

For tetrahydropyridines X which are not commercially available may besynthesized by coupling protected bromophenols XV with protectedunsaturated piperidineboronic acids XVI, as shown in synthetic scheme4a.

For tetrahydropyridines X which are not commercially available may besynthesized by adding the anion generated from protected bromophenols XVto a protected 4-piperidinone XVII to yield 4-phenyl-4-piperidinolXVIII, which may be dehydrated under acid conditions to yield thedesired X, as shown in synthetic scheme 4b.

1-Phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V may be condensedwith isolated individual enantiomers VIIIa-c*, which results indiastereomers 1-phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones IX*,which may be deprotected and separated to give final products Ia*, asshown in scheme 5.

Alternatively, the backbone scaffold may be synthesized by condensing1-phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V withhydroxypiperidines VIIIa to yield the protected 3-fluoropiperidines IXa,which may themselves be converted to the protected 3-fluoropiperidinesIXb or oxidized to the ketones XIX, which may be converted to the3,3-difluoropiperidines Ixc, as shown in scheme 6.

The final compounds can then be isolated after the deprotection ofIXa-c.

DESCRIPTION OF SPECIFIC EMBODIMENTS

Abbreviations used in the schemes generally follow conventions used inthe art. Chemical abbreviations used in the specification and examplesare defined as follows: “NaHMDS” for sodium bis(trimethylsilyl)amide;“DMF” for N,N-dimethylformamide; “MeOH” for methanol; “NBS” forN-bromosuccinimide; “Ar” for aryl; “TFA” for trifluoroacetic acid; “DCM”for dichloromethane; “LAH” for lithium aluminum hydride; “BOC” fort-butoxycarbonyl, “DMSO” for dimethylsulfoxide; “h” for hours; “EtOAc”for ethyl acetate; “THF” for tetrahydrofuran; “EDTA” forethylenediaminetetraacetic acid; “Et₂O” for diethyl ether; “DMAP” for4-dimethylaminopyridine; “DCE” for 1,2-dichloroethane; “ACN” foracetonitrile; “DME” for 1,2-dimethoxyethane; “HOBt” for1-hydroxybenzotriazole hydrate; “DIEA” for diisopropylethylamine, “Nf”for CF₃(CF₂)₃SO₂—; and “TMOF” for trimethylorthoformate.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “satd.” for saturated, “MW” for molecular weight,“mp” for melting point, “ee” for enantiomeric excess, “MS” or “MassSpec” for mass spectrometry, “ESI” for electrospray ionization massspectroscopy, “HR” for high resolution, “HRMS” for high resolution massspectrometry, “LCMS” for liquid chromatography mass spectrometry, “HPLC”for high pressure liquid chromatography, “RP HPLC” for reverse phaseHPLC, “TLC” or “tlc” for thin layer chromatography, “SFC” forsupercritical fluid chromatography, “NMR” for nuclear magnetic resonancespectroscopy, “1H” for proton, “δ” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, and “R”, “S”, “E”, and “Z” are stereochemicaldesignations familiar to one skilled in the art.

LC-MS Methods: Method A:

Column: XBridge Phe 8, 4.6×30 mm, 5 μm; Solvent A=2% AcCN: 98% H2O: 10mM NH₄COOH; Solvent B=98% AcCN: 2% H2O: 10 mM NH₄COOH; gradient 0-100% Bover 1.5 min; 3.2 min run time.

Method B:

Column: ZORBAX SB C18, 4.6×50 mm, 5 μm; Solvent A=10% MeOH: 90% H2O:0.1% TFA; Solvent B=90% AcCN: 10% H2O: 0.1% TFA; gradient 0-100% B over2 min; 3 min run time.

Method C:

Column: ZORBAX SB AQ, 4.6×50 mm, 3.5 rpm; Solvent A=10% MeOH: 90% H2O:0.1% TFA; Solvent B=90% AcCN: 10% H2O: 0.1% TFA; gradient 0-100% B over2 min; 3 min run time.

Method D:

Column: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% AcCN: 90%H2O: 20 mM NH4OAc; Solvent B=90% AcCN: 10% H2O: 20 mM NH4COOH; gradient0-100% B over 1.5 min; 3.2 min run time.

Method E: Column: Ascentis Express C18, 50×4.6 mm, 5 μm; Solvent A=2%AcCN: 98% H2O: 10 mM NH4COOH; Solvent B=98% AcCN: 2% H2O: 10 mM NH4COOH;

-   -   gradient 0-100% B over 1.5 min.

Method F:

Column: Ascentis Express C18, 50×2.1 mm, 2.7 μm; Solvent A=2% AcCN: 98%H2O: 10 mM NH4COOH; Solvent B=98% AcCN: 2% H2O: 10 mM NH4COOH; gradient0-100% B over 1.5 min.

Method G:

Column: XBridge Phenyl, 4.6×150 mm, 3.5 μm; Solvent A=5% AcCN: 95% H2O:0.05% TFA pH=2.5; Solvent B=95% AcCN: 5% H2O: 0.05% TFA pH=2.5; gradient0-100% B.

Method H:

Column: Sunfire C18, 4.6×150 mm, 3.5 μm; Solvent A=5% AcCN: 95% H2O:0.05% TFA pH=2.5; Solvent B=95% AcCN: 5% H2O: 0.05% TFA pH=2.5; gradient0-100% B.

Method I:

Column: Eclipse XDB C18, 4.6×150 mm, 3.5 μm; Solvent A=20 mM NH4Oac inwater; Solvent B=AcCN: Gradient 0-100%.

Method J:

Column: Acquity UPLC BEH C18, 50×2.1 mm, 1.7 μm; Solvent A=0.1% TFA inwater; Solvent B: 0.1% TFA in AcCN; gradient 2-98% B over 1.6 min.

Method K:

Column: Ascentis Express C8, 50×2.1 mm, 2.7 μm; Solvent A=2% AcCN: 98%H2O: 10 mM NH4COOH; Solvent B=98% AcCN: 2% H2O: 10 mM NH4COOH; gradient0-100% B over 1.5 min).

Method L:

Column: ACE Excel 2 C18, (50×3.0 mm-2 μm); Solvent A=2% ACN-98% H2O: 10mM NH4COOH; Solvent B=98% ACN:2% H2O: 10 mM NH4COOH; gradient 0-100% Bover 1.8 min) Flow=1.2 mL/min T=40 C Method M:Column: X-Bridge BEH C18; 50×2.1 mm, 2.5 u; Solvent A: 2% ACN-98%H20-0.1% TFA; Solvent B: 98% ACN-2% H20-0.1% TFA Flow: 1.2 ml/min; T=50C Time (min.); gradient 0-100% B over 2.6 min Method N:Column: Ascentis Express C18 4.6×50 mm, 2.7 μm; Solvent A: 5:95Acetonitrile:water with 10 mM NH4OAc; Solvent B: 95:5 Acetonitrile:waterwith 10 mM NH4OAc; Temperature: 50° C.; Gradient: 0-100% B over 4minutes; Flow: 4.0 ml/min.

Method O:

Column: Ascentis Express C18 4.6×50 mm, 2.7 μm; Solvent A: 5:95Acetonitrile:water with 0.05% TFA; Solvent B: 95:5 Acetonitrile:waterwith 0.05% TFA; Temperature: 50° C.; Gradient: 0-100% B over 4 minutes;Flow: 4.0 ml/min Method P:Column: Acquity BEH C18 (2.1×50 mm) 1.7 u; Buffer: 10 mM AmmoniumAcetate pH 5 adjusted with HCOOH; Solvent A: Buffer: ACN (95:5); SolventB: Buffer: ACN (5:95); Gradient: % B: O min-5%:1.1 min-95%:1.7 min-95%Method 0:Column: Ascentis Express C18 2.1×50 mm, 2.7 μm; Solvent A: 5:95Acetonitrile:water with 0.1% TFA; Solvent B: 95:5 Acetonitrile:waterwith 0.05% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes;Flow: 1.1 ml/min Method S:Column: Xbridge C18 (50×2.1 mm) 2.5 u; Solvent A: 10 mM NH4COOH; SolventB Acetonitrile, gradient 0-100% B over 1.7 minutes, 100% B for 1.5minutes Method T:Column: Phenomenex LUNA C18, 50×2, 3 um; Solvent A: 5% ACN:95% Water:10mM Ammonium Acetate; Solvent B: 95% ACN:5% Water:10 mM Ammonium Acetate;Gradient: 0-100% B over 4 min Method U:Column: PHENOMENEX-LUNA 2.0×50 mm 3 um; Solvent A: 95% Water:5%methanol:0.1% TFA; Solvent B=5% Water:95% methanol:0.1% TFA; Gradient0-100% B over 4 min

Method V

Column: Xbridge BEH C18 (2.1×50 mm), 2.5 μm; Solvent A: 0.1%HCOOH/water; Solvent B: 0.07% HCOOH/acetonitrile; Gradient 0-100% B over1.5 min, stop time 4 min Method 100:Column: Xbridge C₁₈ 4.6×50 mm, 5 μm; Solvent A: water with 10 mM NH₄OAc;Solvent B: methanol; Gradient: 5-95% B over 4 minutes; Flow: 4.0 ml/min.

Method 107

Column: Xbridge C₁₈ 2.1×50 mm, 2.5 μm; Solvent A: water with 10 mMNH₄HCO₃; Solvent B: Acetonitrile; Gradient: 0-100% B over 1.7 minutes;then 100% B for 1.5 min.

Method 109

Column: Kinetex C₁₈ 2.1×50 mm, 2.6 μm; Solvent A: 2:98acetonitrile/water with 10 mM ammonium formate; Solvent B: 98:2acetonitrile/water with 10 mM ammonium formate; Gradient: 0-100% B over1.7 minutes; then 100% B for 1.5 min.

CZ-1:

Column: Waters Aquity UPLC BEH C₁₈ 2.1×50 mm 1.7 μm; Solvent A: 100%water:0.05% TFA; Solvent B: 100% acetonitrile:0.05% TFA; Gradient: 2 to98% B over 1.5 minutes

CZ-2

Column: X-BRIDGE C₁₈ 2.1×50 mm, 3.5 um; Solvent A:5% Water:95%methanol:0.1% TFA; Solvent B: 95% Water:5% methanol:0.1% TFA; Gradient:0 to 100% B over 4 minutes

Chiral HPLC Methods: Method A:

Column: CHIRALPAK AD-H (250×4.6) mm 5 μm; Mob. Phase: 0.2% DEA inn-hexane: IPA (80:20)

Method A-2:

Column: CHIRALPAK AD-H (250×21) mm, 5 μm; Mob. Phase: 0.2% DEA inn-hexane: IPA (70:30)

Method A-3:

Column: CHIRALPAK AD-H (250×4.6) mm, 5 μm; Mob. Phase: 0.2% DEA inn-hexane: IPA (70:30)

Method A-4:

Column: CHIRALPAK AD-H (250×4.6) mm, 5 μm; Mob. Phase: 0.2% DEA inn-hexane: IPA (50:50)

Method B:

Column: CHIRALPAK-ASH (250×4.6) mm, 5 μm; Mob. Phase: 0.2% DEA inn-hexane:ethanol (70:30)

Method C:

Column: CHIRALPAK IC (250×4.6) mm, 5 μm; Mob. Phase: 0.1% TFA inn-hexane:ethanol (40:60)

Method D:

Column: CHIRALPAK IA (250×4.6) mm, 5 μm; Mob. Phase: 0.1% TFA inhexane:ethanol (50:50)

Method E:

Column: CHIRALPAK IC (250×4.6) mm, 5 μm; Mob. Phase: 0.05% TFA inH₂O:acetonitrile (80:20)

Method F:

Column: CHIRALCEL ODH (250×4.6) mm, 5 μm; Mob. phase: 0.2% DEA inn-hexane:ethanol (30:70)

Method G (SFC):

Column: Lux Cellulose-2, (4.6×250) mm, 5 μm; co-solvent 0.3% DEA inmethanol; flow rate 2.55 g/min, 15% co-solvent, back pressure 100 bar

Method G-2 (SFC):

Column: Lux Cellulose-2, (4.6×250) mm, 5 μm; co-solvent 0.3% DEA inmethanol, flow rate 2.55 g/min, 10% co-solvent, back pressure 100 bar

Method H:

Column: Chiralcel OJ (21×250 mm) 10 μm; Mob. Phase 0.1%diethylamine/heptane:ethanol (40:60)

Method H-2:

Column: Chiralcel OJ (4.6×100 mm) 10 μm; Mob. Phase 0.1%diethylamine/heptane:ethanol (40:60)

Method H-3:

Column: Chiralcel OJ (4.6×250 mm) 5 μm; Mob. Phase 0.1%diethylamine/hexane:ethanol (50:50)

Method H-4:

Column: Chiralcel OJ (4.6×250 mm) 5 μm; Mob. Phase 0.2%diethylamine/hexane:ethanol (50:50)

Chiral SFC Methods: Method A1:

Column: CHIRALPAK IC; Co Solvent: 0.5% DEA in methanol; Co Solvent %:50; Total flow: 3 g/min; Back pressure: 93 bar.

Method A2:

Column: CHIRALPAK IC; Co Solvent: 0.5% DEA in methanol; Co Solvent %:50; Total flow: 3 g/min; Back pressure: 100 bar;

Method A3:

Column: CHIRALPAK IC; Co Solvent: 0.5% DEA in methanol; Co Solvent %:40; Total flow: 3 g/min; Back pressure: 101 bar

Method A4:

Column: CHIRALPAK IC; Co Solvent: 0.5% DEA in methanol; Co Solvent %:40; Total flow: 3 g/min; Back pressure: 101 bar

Method A5:

Column: CHIRALPAK IC; Co Solvent: 0.5% DEA in methanol; Co Solvent %:20; Total flow: 3 g/min; Back pressure: 101 bar

Method B 1:

Column: CHIRALCEL OD H; Co Solvent: 0.5% DEA in methanol; Co Solvent %:30; Total flow: 3 g/min; Back pressure: 100 bar

Method C1:

Column: CHIRALPAK AD H; Co Solvent: 0.5% DEA in methanol; Co Solvent %:20; Total flow: 3 g/min; Back pressure: 100 bar

Method C2:

Column: CHIRALPAK AD H; Co Solvent: 0.5% DEA in methanol; Co Solvent %:20; Total flow: 3 g/min; Back pressure: 99 bar

Method C3:

Column: CHIRALPAK AD H; Co Solvent: 0.5% DEA in methanol; Co Solvent %:40; Total flow: 3 g/min; Back pressure: 97 bar

Method C4:

Column: CHIRALPAK AD H; Co Solvent: 0.5% DEA in methanol; Co Solvent %:30; Total flow: 3 g/min; Back pressure: 102 bar

Method C5:

Column: CHIRALPAK AD H (250×4.6 mm, 5u); Co Solvent: 0.3% DEA inmethanol; Co Solvent %: 30; Total flow: 3 g/min; Back pressure: 102 bar

Method C6:

Column: CHIRALPAK AD H (250×4.6 mm, 5u); Co Solvent: 0.3% DEA inmethanol; Co Solvent %: 45; Total flow: 3 g/min; Back pressure: 102 bar

Method C7:

Column: CHIRALPAK AD H (250×21 mm, 5u); Co Solvent: 0.3% DEA inmethanol; Co Solvent %: 45; Total flow: 60 g/min; Back pressure: 102bar.

Method C8:

Column: CHIRALPAK AD H (250×21 mm, 5u); Co Solvent: 0.3% DEA inmethanol; Co Solvent %: 30; Total flow: 60 g/min; Back pressure: 102bar.

Method D:

Column: Lux Cellulose-2 (250×21.2) mm, 5u; Co Solvent: 0.3% DEA inmethanol; Co Solvent %: 20; Total flow: 60 g/min; Back pressure: 100bar.

Method E:

Column: CHIRALPAK AS H (250×4.6 mm, 5u); Co Solvent: 0.3% DEA inmethanol; Co Solvent %: 60; Total flow: 3 g/min; Back pressure: 102 bar.

Method F:

Column: CHIRALPAK AS H (250×4.6 mm, 5u); Co Solvent: 0.3% DEA inmethanol; Co Solvent 30%; Total flow: 3 g/min; Back pressure: 102 bar.

Method G:

Column: Whelk O1 (R,R), 250×4.6 mm, 5u; Co-solvent 0.3% DEA in methanol,cosolvent 35%; total flow 4 g/min, backpressure 102 bar

Method H:

Column: Whelk O1 (R,R), 250×4.6 mm, 5u; Co-solvent 0.3% DEA in methanol,cosolvent 30%; total flow 4 g/min, backpressure 102 bar

Method H-1:

Column: Whelk O1 (R,R), 250×30 mm, 5u; Co-solvent 0.3% DEA in methanol,cosolvent 25%; total flow 120 g/min, backpressure 102 bar

Method I:

Column: CHIRALPAK AS H (250×4.6 mm, 5u); Co Solvent: 0.3% DEA inmethanol; Co Solvent 35%: Total flow: 3 g/min; Back pressure: 102 bar.

Method J:

Column: CHIRALPAK AS H (250×4.6 mm, 5u); Co Solvent: 0.3% DEA inmethanol; Co Solvent 20%; Total flow: 3 g/min; Back pressure: 102 bar.

Method K:

Column: CHIRALPAK AS H (250×4.6 mm, 5u); Co Solvent: 0.3% DEA inmethanol; Co Solvent 40%; Total flow: 80 g/min; Back pressure: 102 bar.

Method L:

Column: CHIRALPAK AS H (250×4.6 mm, 5u); Co Solvent: 0.3% DEA inmethanol; Co Solvent 25%; Total flow: 100 g/min; Back pressure: 102 bar.

Method 101:

Column: Lux Cellulose-2 (250×21.2) mm, 5u; Co Solvent: 0.3% DEA inmethanol; Co Solvent %: 40; Total flow: 70 g/min; Back pressure: 100bar.

Method 104:

Column: CHIRALPAK AD H (250×30 mm, 5 μm); Co Solvent: 0.3% DEA inmethanol; Co Solvent %: 40; Total flow: 70 g/min; Back pressure: 100bar.

Method 105:

Column: CHIRALPAK AD H (250×4.6 mm, 5u); Co Solvent: 0.3% DEA inmethanol; Co Solvent %: 45; Total flow: 3 g/min; Back pressure: 100 bar.

Method 106:

Column: CHIRALPAK AD H (250×4.6 mm, 5u); Co Solvent: 0.3% DEA inmethanol; Co Solvent %: 40; Total flow: 4 g/min; Back pressure: 100 bar.

Method 108:

Column: CHIRALPAK AS H (250×4.6 mm, 5u); Co Solvent: 0.3% DEA inmethanol; Co Solvent %: 30; Total flow: 3 g/min; Back pressure: 100 bar.

Analytical HPLC Methods: Method A:

Column: Waters analytical C18 Sunfire (4.6×150 mm, 3.5 μm); Mobilephase: Buffer: 0.05% TFA in H₂O pH=2.5 adjusted with ammonia; SolventA=buffer and acetonitrile (95:5), Solvent B=acetonitrile and buffer(95:5); 0-15 min, 0% B→50% B; 15-18 min, 50% B→100% B; 18-23 min, 100%B; flow rate=1 mL/min; run time=28 min.

Method B:

Column: Waters analytical phenyl Xbridge column (4.6×150 mm, 3.5 μm);Mobile phase: Buffer: 0.05% TFA in H₂O pH=2.5 adjusted with ammonia;Solvent A=buffer and acetonitrile (95:5), Solvent B=acetonitrile andbuffer (95:5); 0-15 min, 0% B→50% B; 15-18 min, 50% B→100% B; 18-23 min,100% B; flow rate=1 mL/min; run time=28 min.

Method C:

Column: Waters analytical C18 Sunfire (4.6×150 mm, 3.5 μm); Mobilephase: Buffer: 0.05% TFA in H₂O pH=2.5 adjusted with ammonia; SolventA=buffer and acetonitrile (95:5), Solvent B=acetonitrile and buffer(95:5); 0-12 min, 10% B→100% B; 12-15 min, 100% B; flow rate=1 mL/min;run time=17 min.

Method D:

Column: Waters analytical phenyl Xbridge column (4.6×150 mm, 3.5 μm),mobile phase: Buffer: 0.05% TFA in H₂O pH=2.5 adjusted with ammonia;solvent A=buffer and acetonitrile (95:5), Solvent B=acetonitrile andbuffer (95:5); 0-12 min, 10% B→100% B; 12-15 min, B→100% B; flow rate=1mL/min; run time=17 min.

Method E:

Column: Waters analytical phenyl Xbridge (4.6×150 mm, 3.5 μm), Mobilephase: Solvent A=10 mM NH₄HCO₃ in H₂O, pH=9.5 adjusted with ammonia,Solvent B=methanol; 0-12 min, 10% B→100% B; 12-20 min, B→100% B; flowrate=1 mL/min; run time=23 min.

Method F:

Column: Waters analytical C18 Sunfire (4.6×150 mm, 3.5 μm); Mobilephase: Buffer: 0.05% TFA in H₂O pH=2.5 adjusted with ammonia, SolventA=buffer and acetonitrile (95:5), Solvent B=acetonitrile and buffer(95:5); 0-25 min, 10% B→100% B; 25-30 min, 100% B; flow rate=1 mL/min;run time=32 min.

Method G:

Column: ECLIPSE XDB C18 (4.6×150 mm, 3.5 μm); Mobile phase; Solvent A=20mM NH₄OAc in H₂O, Solvent B=acetonitrile; 0-12 min, 10% B→100% B; 12-15min, 100% B; flow rate=1 mL/min; run time=18 min.

Method H:

Column: Waters analytical phenyl Xbridge (4.6×150 mm, 3.5 μm); Mobilephase: Buffer: 0.05% TFA in H₂O pH=2.5 adjusted with ammonia, solventA=buffer and acetonitrile (95:5), Solvent B=acetonitrile and buffer(95:5); 0-25 min, 10% B→100% B; 25-30 min, 100% B; flow rate=1 mL/min;run time=32 min.

Method I:

Column: Waters analytical phenyl Xbridge (4.6×150 mm, 3.5 μm), Mobilephase: A=10 mM NH₄HCO₃ in H₂O pH=9.5 adjusted with ammonia, B=methanol;0-25 min, 10% B→100% B; 25-30 min, B→100% B; flow rate=1 mL/min; runtime=30 min.

Method J:

Column: ECLIPSE XDB C₁₈ (4.6×150 mm, 5 μm); Mobile phase: A=20 mM NH₄OAcin H₂O, B=acetonitrile; 0-25 min, 10% B→100% B; 25-30 min, 100% B; flowrate=1 mL/min; run time=30 min.

Method K:

Column: Waters analytical phenyl Xbridge (4.6×150 mm, 3.5 μm), Mobilephase: A=10 mM NH₄HCO₃ in H₂O pH=9.5 adjusted with ammonia, B=methanol;0-15 min, 0% B→50% B; 15-18 min, 50%-100% B; 18-23 min, 100% B; flowrate=1 mL/min; run time=25 min.

Method L:

Column: ECLIPSE XDB C₁₈ (4.6×150 mm, 5 μm); mobile phase: A=20 mM NH₄OAcin H₂O, B=acetonitrile; 0-15 min, 0% B→50% B; 15-18 min, 50%→100% B;18-23 min, 100% B; flow rate=1 mL/min; run time=25 min.

Method M:

Column: Waters analytical phenyl Xbridge C₁₈ (4.6×150 mm, 3.5 μm),Mobile phase: A=20 mM NH4OAc in H₂O, B=acetonitrile; 0-25 min, 10%B→100% B; 25-30 min, B→100% B; flow rate=1 mL/min; run time=30 min.

Method N:

Column: Waters analytical phenyl Xbridge C₁₈ column (4.6×150 mm, 3.5μm), Mobile phase: A=20 mM NH₄OAc in H₂O, B=acetonitrile; 0-12 min, 10%B→100% B; 12-15 min, B→100% B; flow rate=1 mL/min; run time=20 min.

Method O:

Column: Ascentis Express C₁₈ (50×2.1 mm-2.7 μM); Solvent A: 2% ACN-98%H20-10 mM NH₄COOH, Solvent B: 98% ACN-2% H20-10 mM NH₄COOH; Gradient0-100% B over 1.7 min, stop time 3.4 min.

Method P:

Column: XBridge Phenyl (150×4.6 mm) 3.5 μM; Mobile phase A:0.05% TFA inwater:Acetonitrile (95:5), Mobile phase B: Acetonitrile:0.05% TFA inwater (95:5); Gradient 10-100% B over 12 min, stop time 15 min.

Method 102

Column: Ascentis Express c 18 (50×2.1 mm-2.7 μM); Solvent A: 5% ACN-95%H20-10 mM NH₄COOH, Solvent B: 95% ACN-5% H20-10 mM NH₄COOH, Gradientfrom 0-100% B over 3 minutes.

Preparative HPLC Methods: Method A:

Column: Symmetry C₈ (300×19 mm×7); Mobile phase A: 10 mM aqueousammonium acetate, mobile phase B: methanol; Isocratic run with 25% B inA; run time=20 minutes

Method B:

Column: Waters Xbridge C₁₈, 19×150 mm, 5 μm; Guard Column: WatersXBridge C₁₈, 19×10 mm, 5 μm; Mobile Phase A: 5:95 acetonitrile:waterwith 10 mM NH4OAc; Mobile Phase B: 95:5 Acetonitrile:water with 10 mMNH₄OAc; Gradient: 10-40% B over 25 minutes, followed by a 10 minute holdat 40% B and 5 minute hold at 100% B;

Method C:

Column: ODS (250×4.6 mm), 3.5u; Mobile phase A: 10 mM ammoniumacetate/water; Mobile phase B acetonitrile; gradient 50-100% B in A over25 min

Method D:

Column: Waters Xbridge C₁₈, 19×150 mm, 5 μm; Guard Column: WatersXBridge C₁₈, 19×10 mm, 5 μm; Mobile Phase A: 5:95 methanol:water with0.1% TFA; Mobile Phase B: 95:5 methanol:water with 0.1% TFA; Gradient:10-30% B over 25 minutes, followed by a 10 minute hold at 30% B and 5minute hold at 100% B;

Method E:

Column: Symmetry C18 (300×19 mm×7 u); Mobile phase A 10 mM aqueousammonium acetate, mobile phase B acetonitrile; flow rate=16 mL/min,gradient run 20-55% B in A over 10 min; λ=220 nm; run time=20 minutes

Method F:

Column: Xterra RP₁₈ (250×19 mm, 5u); Mobile phase A: 10 mM ammoniumacetate pH 4.5, Mobile phase B: acetonitrile. Flow 15 ml/min

Method 103:

Column: Sunfire C18 (150×4.6 mm×5 u); Mobile phase A 10 mM aqueousammonium acetate, Mobile phase B acetonitrile; Gradient 0-100% B over 18minutes; run time=20 minutes.

General Intermediates1-Benzyl-3-bromopyrrolidin-2-ones/1-benzyl-3-bromopiperidin-2-ones

The synthetic intermediates in Table 1 were synthesized by a procedureanalogous to that reported in A. Kamal, et. al., Tetrahedron: Asymmetry,2003, 14, 2587-2594, using substituted benzylamines and the appropriatedibromo-alkanoyl chloride.

Representative Procedure (Intermediate 6) Intermediate 6,3-Bromo-1-(3-fluoro-4-methyl-benzyl)pyrrolidin-2-one Step A

To a stirring 0° C. solution of 3-fluoro-4-methylbenzyl amine (2.0 g, 14mmol) and N-ethyl-N-isopropylpropan-2-amine (3.5 mL, 20 mmol) indichloromethane (30 mL) was added dropwise a solution of2,4-dibromobutanoyl chloride (3.98 g, 15 mmol) in dichloromethane (5mL). After completion of the addition, the reaction was stirred in theice bath until all of the ice had melted, then it was partitionedbetween ethyl acetate and water. The layers were separated, the organiclayer was washed with brine, and it was then dried over magnesiumsulfate. The drying agent was filtered off, the solvent was evaporated,and the residue was dissolved in ethyl acetate and subjected to silicagel chromatography in 10->25->100% ethyl acetate/hexane, collecting themain component to yield 4.5 g (85%)2,4-dibromo-N-(3-fluoro-4-methylbenzyl)butanamide. LCMS (method CZ-1):RT 1.21 min, m/z 367.9 (MH⁺); ¹H NMR (500 MHz, chloroform-d) δ 7.17 (t,J=7.7 Hz, 1H), 7.01-6.91 (m, 2H), 6.70 (br. s., 1H), 4.59 (dd, J=9.0,4.9 Hz, 1H), 4.51-4.37 (m, 2H), 3.64-3.51 (m, 2H), 2.71 (dddd, J=15.0,8.5, 6.1, 4.9 Hz, 1H), 2.51 (ddt, J=15.0, 9.2, 5.5 Hz, 1H), 2.27 (d,J=1.4 Hz, 3H).

Step B

To a stirring suspension of NaH (0.76 g, 19 mmol) in tetrahydrofuran (50mL) was added dropwise over ˜½ hour a solution of2,4-dibromo-N-(3-fluoro-4-methylbenzyl)butanamide (4.5 g, 12.2 mmol) intetrahydrofuran (30 mL) and the resulting mixture was stirred at roomtemperature overnight. The reaction mixture was then filtered and thesolvent evaporated.

The residue was subjected to silica gel chromatography in 10-50% ethylacetate/hexane, collecting 949 mg recovered starting material and 2.28 g3-bromo-1-(3-fluoro-4-methyl-benzyl)pyrrolidin-2-one (Intermediate #6)as a white solid.

TABLE 1 Substituted 1-benzyl-3-bromo-pyrrolidin-2-ones/1-benzyl-3-bromopiperidin-2-ones LCMS (Method) Int. RT LCMS No. Structure (min)[M + H]⁺ ¹H NMR  1

(P) 0.85 272.4/ 274.3 ¹H NMR (400 MHz, DMSO- d₆) δ ppm 2.12-2.27 (m, 1H) 2.56-2.68 (m, 1 H) 3.27 (dd, J = 7.78, 3.26 Hz, 2 H) 4.29- 4.38 (m, 1H) 4.40-4.57 (m, 1 H) 4.73 (dd, J = 7.03, 3.01 Hz, 1 H) 7.04-7.35 (m, 4H)  2

(V) 2.30 268/ 270 ¹H NMR (400 MHz, chloroform-d) δ ppm 2.20- 2.30 (m, 1H) 2.34 (s, 3 H) 2.54 (s, 1 H) 3.19 (s, 1 H) 3.36-3.45 (m, 1 H) 4.36-4.54 (m, 3 H) 7.15 (s, 4 H)  2a

(K) 1.89 304/ 306 ¹H NMR (400 MHz, DMSO- d₆) δ ppm 7.58 (d, J = 8.03 Hz,2 H) 7.40 (d, J = 8.53 Hz, 2 H) 7.03 (m, 1 H) 4.75 (dd, J = 7.53, 3.01Hz, 1 H) 4.52- 4.59 (m, 1 H) 4.41-4.47 (m, 1 H) 3.33-3.39 (m, 1 H) 3.25-3.32 (m, 1 H) 2.65 (dq, J = 14.62, 7.34 Hz, 1 H) 2.21 (ddt, J = 14.43,6.65, 3.26, 3.26 Hz, 1 H)  3

(P) 0.90 254.0/ 256.0 300 MHz, DMSO-d6: δ 2.15- 2.24 (m, 1H), 2.49-2.52(m, 1H), 3.23-3.28 (m, 2H), 4.35 (d, J = 15.00 Hz, 1H), 4.51 (d, J =15.00 Hz, 1H), 4.74 (dd, J = 3.00, 7.20 Hz, 1H), 7.23- 7.40 (m, 5H)  4

300 MHz, DMSO-d6: δ 1.49 (dd, J = 3.30, 7.20 Hz, 3H), 2.11-2.18 (m, 1H),2.49-2.63 (m, 1H), 2.95-3.03 (m, 1H), 3.38-3.41 (m, 1H), 4.71 (dd, J =3.00, 7.20 Hz, 1H), 5.22- 5.24 (m, 1H), 7.28-7.41 (m, 5H),  5

300 MHz, DMSO-d6: δ 1.49 (d, J = 7.20 Hz, 3H), 2.11- 2.18 (m, 1H),2.53-2.63 (m, 1H), 2.95-3.03 (m, 1H), 3.35- 3.41 (m, 1H), 4.70 (dd, J =3.0, 7.20 Hz, 1H), 5.22-5.24 (m, 1H), 7.28-7.41 (m, 5H)  6

(P) 0.90 286.3/ 288.3 ¹H NMR (400 MHz, chloroform -d) δ ppm 2.26 (d, J =2.01 Hz, 5 H) 2.48-2.64 (m, 1 H) 3.20 (s, 1 H) 3.38- 3.49 (m, 1 H)4.29-4.55 (m, 3 H) 6.92 (s, 2 H) 7.15 (s, 1 H)  7

300 MHz, DMSO-d6: δ 1.90- 2.18 (m, 1H), 2.20-2.29 (m, 1H), 2.32-2.33 (m,1H), 2.59- 2.62 (m, 1H), 2.88-3.01 (m, 3H), 3.21-3.25 (m, 1H), 4.74 (dd,J = 2.70, 6.90 Hz, 1H), 5.57 (t, J = 7.80 Hz, 1H), 7.08-7.11 (m, 1H),7.23-7.32 (m, 3H)  8

(J) 0.92 282.0/ 284.0  9

(P) 0.97 288.4/ 290.3 ¹H NMR (400 MHz, chloroform-d) δ ppm 7.32 (d, J =8.4, 2H), 7.20 (d, J = 8.4, 2H), 4.54 (d, J = 14, 1H), 4.48 (m, 1H),4.74 (d, J = 14, 1H), 3.45-3.39 (m, 1H), 3.22-3.17 (m, 1H), 2.59-2.54(m, 1H), 2.33-2.27 (m, 1H), 10

(V) 1.94 306.0/ 307.9 400 MHz, MeOD: δ 2.34-2.29 (m, 1H), 2.67-2.72 (m,1H), 3.39-3.32 (m, 1H), 3.52-3.46 (m, 1H), 4.42 (d, J = −15.20 Hz, 1H),4.61 (d, J = −24.80 Hz, 2H), 7.17 (dd, J = −41.60, Hz, 2H), 7.48 (t, J =−15.60 Hz, 1H) 11

(S) 1.85 289.9/ 291.9 400 MHz, DMSO-d6: δ 7.41- 7.48 (m, 1H), 7.28-7.34(m, 1H), 7.10-7.13 (m, 1H), 4.73- 4.76 (m, 1H), 4.36-4.50 (m, 2H),3.27-3.31 (m, 2H), 3.36- 3.39 (m, 1H), 2.62-2.68 (m, 1H), 2.18-2.23 (m,1H) 12

(K) 1.96 320.0/ 322.0 400 MHz, DMSO-d6: δ 6.98- 7.47 (m, 4H), 4.73 (dd,J = 14.00, Hz, 1H), 4.49 (d, J = 19.60 Hz, 1H), 4.35 (d, J = 20.00 Hz,1H), 3.22-3.29 (m, 2H), 2.56-2.68 (m, 1H), 2.15- 2.23 (m, 1H) 13

(V) 3.14 282.0/ 284.0 ¹H NMR (400 MHz, chloroform -d) δ ppm 2.26 (d, J =2.01 Hz, 5 H) 2.48-2.64 (m, 1 H) 3.20 (s, 1 H) 3.38- 3.49 (m, 1 H)4.29-4.55 (m, 3 H) 6.92 (s, 2 H) 7.15 (s, 1 H) 14

(V) 2.02 302.0/ 304.0 15

(F) 1.97 268.3/ 270.2 ¹H NMR 400 MHz, MeOD: δ ppm 7.26-7.21 (m, 1H),7.13- 7.05 (m, 2H), 4.62-4.53 (m, 2H), 4.35 (d, J = 14.7, 1H), 3.47-3.38(m, 1H), 3.31-3.25 (m, 1H), 2.70-2.58 (m, 1H), 2.33-2.18 (m, 4H) 16

(V) 1.73 284.0/ 286.1 ¹H NMR 300 MHz, MeOD: δ ppm 7.22 (d, J = 6.6, 2H),6.91 (d, J = 6.6, 2H), 4.60 (m, 1H), 4.54 (d, J = 15, 1H), 4.34 (d, J =15, 1H), 3.78 (s, 3H), 3.46- 3.38 (m, 1H), 3.31-3.26 (m, 1H), 2.70-2.58(m, 1H), 2.31- 2.23 (m, 1H) 17

(P) 0.82/ 0.84 268.3/ 270.3 ¹H NMR (300 MHz, DMSO- d₆) δ ppm 1.67-1.86(m, 1 H) 1.90-2.19 (m, 2 H) 2.25- 2.42 (m, 1 H) 3.23-3.32 (m, 2 H) 4.41(s, 1 H) 4.61 (s, 1 H) 4.73-4.85 (m, 1 H) 7.12- 7.44 (m, 5 H) 18

(P) 0.92 282.3/ 284.3 ¹H NMR (400 MHz, DMSO- d₆) δ ppm 1.67-1.84 (m, 1H) 1.92-2.04 (m, 1 H) 2.04- 2.17 (m, 1 H) 2.29 (s, 4 H) 3.19-3.28 (m, 2H) 4.24- 4.37 (m, 1 H) 4.53-4.64 (m, 1H) 4.72-4.82 (m, 1 H) 7.14 (d, J =4.02 Hz, 4 H) 19

(P) 0.96 300.0/ 302.0 ¹H NMR (400 MHz, DMSO- d₆) δ ppm 1.65-1.85 (m, 1H) 1.99 (s, 1 H) 2.21 (d, J = 1.51 Hz, 1 H) 2.27-2.40 (m, 3 H) 2.59-2.26(s, 1 H) 3.24-3.32 (m, 2H) 4.36 (d, J = 15.06 Hz, 1 H) 4.57 (d, J =15.06 Hz, 1 H) 4.79 (s, 1 H) 6.91-7.05 (m, 2 H) 7.25 (s, 1 H) 20

(P) 0.99 302.3/ 304.3 ¹H NMR (300 MHz, DMSO- d₆) δ ppm 1.68-1.87 (m, 1H) 1.92-2.18 (m, 2 H) 2.22- 2.39 (m, 1 H) 3.20-3.29 (m, 2 H) 4.33-4.45(m, 1 H) 4.53- 4.64 (m, 1 H) 4.74-4.83 (m, 1 H) 7.25-7.33 (m, 2 H) 7.35-7.47 (m, 2 H)

Substituted (4-methoxyphenyl)cycloalkylamines Intermediate 21:4-(4-Methoxyphenyl)azepane Step A tert-Butyl4-hydroxy-4-(4-methoxyphenyl)azepane-1-carboxylate

To a solution of 1-bromo-4-methoxybenzene (0.88 g, 4.7 mmol) in THF (50mL) was added n-butyllithium (2.9 mL, 4.7 mmol) at −78° C. The reactionmixture was stirred at −78° C. for 2 h, then added to a flask containingtert-butyl 4-oxoazepane-1-carboxylate (1 g, 4.7 mmol) in THF, cooled to−78° C. The reaction mixture was stirred at −78° C. for 30 min and thenat 0° C. for 15 min. It was then quenched with saturated ammoniumchloride solution and extracted with ethyl acetate. The organic phasewas dried over sodium sulfate, filtered, and concentrated. The crudeproduct was purified by flash chromatography on silica gel usinghexane/ethyl acetate as the eluant to yield tert-butyl4-hydroxy-4-(4-methoxyphenyl)azepane-1-carboxylate (0.68 g, 45%). LCMS:R.T. 0.96 min. LCMS (ES-API), m/z 320 (M−H).

Step B 5-(4-Methoxyphenyl)-2,3,4,7-tetrahydro-1H-azepine hydrochloride

A mixture of HCl in dioxane (10 mL, 40 mmol) and tert-butyl4-hydroxy-4-(4-methoxyphenyl)azepane-1-carboxylate (0.68 g, 2.1 mmol)was stirred at room temperature for 3 h. The reaction mixture wasconcentrated and washed with diethyl ether and dried over sodium sulfateto yield 0.36 g 5-(4-methoxyphenyl)-2,3,4,7-tetrahydro-1H-azepinehydrochloride. LCMS: R.T. 0.61 min. LCMS (ES-API), m/z 204.0 (M+H).

Step C 4-(4-Methoxyphenyl)azepane

A mixture of 5-(4-methoxyphenyl)-2,3,4,7-tetrahydro-1H-azepinehydrochloride (0.35 g, 1.5 mmol) and 10% palladium on carbon (0.2 g) inmethanol (10 mL) was stirred overnight under balloon pressure ofhydrogen. The reaction mixture was filtered through Celite andconcentrated to yield 4-(4-methoxyphenyl)azepane (0.26 g, 1.2 mmol,79%). LCMS: R.T. 0.60 min. LCMS (ES-API), m/z 206.0 (M+H).

Intermediate 22: 3-(4-Methoxyphenyl)azepane Step A tert-Butyl3-hydroxy-3-(4-methoxyphenyl)azepane-1-carboxylate

To a stirred solution of 1-bromo-4-methoxybenzene (0.67 mL, 5.4 mmol) inTHF (50 mL) at −78° C. was added n-butyllithium (5 mL, 8 mmol) and thereaction mixture was stirred at −78° C. for 2 h. Then was addedtert-butyl 3-oxoazepane-1-carboxylate (1.14 g, 5.4 mmol) at −78° C. andthe reaction mixture was warmed to room temperature over 12 h. It wasthen quenched with saturated NH₄Cl at 0° C., and extracted with ethylacetate. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated. The crude productwas purified by flash chromatography on silica gel (24 g) using 10%ethyl acetate in hexane to yield tert-butyl3-hydroxy-3-(4-methoxyphenyl)azepane-1-carboxylate (1.2 g, 57%) as acolorless gum. LCMS: R.T. 1.03 min. LCMS (ES-API), m/z 204 (M-117).

Step B 6-(4-Methoxyphenyl)-2,3,4,5-tetrahydro-1H-azepine hydrochloride

A solution of tert-butyl3-hydroxy-3-(4-methoxyphenyl)azepane-1-carboxylate (0.25 g, 0.78 mmol)in HCl (4M solution in dioxane) (3 mL, 12 mmol) was stirred at roomtemperature for 5 h. The reaction mixture was concentrated and theresidue was triturated with diethyl ether to yield6-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-azepine hydrochloride (0.18 g,62%) as a black gum. LCMS: R.T. 0.60 min. LCMS (ES-API), m/z 204 (M+1).

Step C 3-(4-Methoxyphenyl)azepane hydrochloride

A mixture of 6-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-azepinehydrochloride (0.3 g, 1.251 mmol) and 10% Pd—C (0.133 g, 1.251 mmol) inmethanol (5 mL), was hydrogenated at 50 psi for 12 h. The reactionmixture was filtered through Celite and concentrated to yield crude3-(4-methoxyphenyl)azepane hydrochloride (0.2 g, 57%) as a black gum,used without further purification. LCMS: RT 0.62 min. LCMS (ES-API), m/z206.1 (M+1).

Intermediate 24: 4-(4-Methoxyphenyl)piperidine hydrochloride Step Atert-Butyl 4-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate

A mixture of tert-butyl 4-oxopiperidine-1-carboxylate (2 g, 10.04 mmol)and diethyl ether (30 ml) was cooled to 0° C., followed by the dropwiseaddition of (4-methoxyphenyl)magnesium bromide (0.5 M in diethyl ether,30 ml, 15 mmol). The reaction mixture was allowed to warm to rt andstirred for 2 h. It was then slowly quenched with 150 ml of ice coldwater and then the resulting mixture was extracted with 3×150 ml of DCM.The organic layers were combined, dried, filtered, and concentratedunder vacuum. The crude product was purified by silica gelchromatography eluting with 30:70 ethyl acetate:hexane to provide 3 gtert-butyl 4-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate (100%).LCMS: RT 1.950 min. LCMS (ES-API), m/z 305.5 (M−H). ¹H NMR (400 MHz,DMSO-d₆) δ 7.37 (q, J=1.0 Hz, 2H), 6.86 (q, J=1.0 Hz, 2H), 4.94 (s, 1H),3.82 (d, J=11.5 Hz, 2H), 3.73 (s, 3H), 3.13 (br. s, 2H), 1.75 (td,J=12.9, 4.8 Hz, 2H), 1.56 (d, J=12.3 Hz, 2H), 1.41 (s, 9H).

Step B 4-(4-Methoxyphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

A mixture of tert-butyl4-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate (700 mg, 2.27mmol) from Step A and HCl in dioxane (4 ml, 16 mmol) was stirred at rtfor 3 h.

The crude mass was concentrated under vacuum and the solid residue waswashed with 3×10 ml of DCM to remove non-polar impurities. The desiredsalt was collected as a fine solid (480 mg, 93%). LCMS: RT 1.27 min.LCMS (ES-API), m/z 190.2 (M+H). NMR: ¹H NMR (400 MHz, DMSO-d₆) δ 7.37(d, J=9.0 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 6.08-5.98 (m, 1H), 5.11 (s,1H), 3.97 (br. s., 1H), 3.52 (s, 1H), 3.32 (s, 3H), 2.47-2.37 (m, 1H).

Step C 4-(4-Methoxyphenyl)piperidine hydrochloride

To a stirred solution of 4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine,HCl (3 g, 13.3 mmol) (from step B) in methanol (20 mL) was added 10%palladium on carbon (1.4 g) and the reaction mixture was stirred at 20psi of hydrogen for 12 h. The reaction mixture was filtered through apad of celite, which was washed with ethyl acetate, and the combinedorganic fractions were concentrated to obtain a white solid (2 g, 70%yield). LCMS (ES-API), m/z 192.1 (M+H); ¹H NMR (300 MHz, DMSO-d₆) δ9.13-8.36 (m, 2H), 7.14 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 3.73(s, 3H), 3.07-2.87 (m, 4H), 2.87-2.65 (m, 4H).

Intermediate 24 trans-4-(4-Methoxyphenyl)piperidin-3-ol Step A:trans-1-Benzyl-4-(4-methoxyphenyl)piperidin-3-ol

To a suspension of sodium tetrahydroborate (2.7 g, 72 mmol) in THF (200mL) 0° C. was added dropwise boron trifluoride etherate (8.8 mL, 70mmol) under a nitrogen atmosphere and the resulting mixture was stirredfor 30 minutes. Then was added1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (10 g, 36 mmol)(from S. Halazy et al WO 97/28140 (8/7/97)) dissolved in 100 mL oftetrahydrofuran. Stirring was continued at rt for 2 hours. The reactionwas then quenched by the dropwise addition of 100 mL water. Next wereadded sequentially 100 mL ethanol, 100 mL 10% aqueous sodium hydroxide,and hydrogen peroxide (18 mL, 18 mmol) and the temperature was raised toreflux overnight. The reaction mixture was diluted with saturatedaqueous ammonium chloride (200 mL), and extracted with ethyl acetate(500 mL). The organic layer was dried over Na₂SO₄, filtered, andevaporated under reduced pressure to givetrans-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (8.5 g, 24.6 mmol, 69%yield). LCMS (Method K) RT 1.99 min; m/z 298.0 (MH⁺).

Step B: trans-4-(4-Methoxyphenyl)piperidin-3-ol

To a solution of trans-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (9 g,30 mmol) in methanol (150 mL) was added 10% Pd/C (4.8 g) and thereaction was stirred overnight under a hydrogen atmosphere. The catalystwas then removed by filtration through Celite and the solvent wasevaporated under reduced pressure to give (+/−)trans-4-(4-methoxyphenyl)-piperidin-3-ol (5.1 g, 24.6 mmol, 81% yield).¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.10-7.15 (m, 2H) 6.80-6.86 (m, 2H) 4.30(d, J=5.27 Hz, 1H) 3.37-3.43 (m, 1H) 3.04 (dd, J=11.58, 4.36 Hz, 1H)2.86 (d, J=12.17 Hz, 1H) 2.43 (td, J=12.09, 2.67 Hz, 1H) 2.22-2.35 (m,2H) 1.57-1.63 (m, 1H) 1.43-1.54 (m, 1H).

Intermediate 25. 3-(4-Methoxyphenyl)piperidine

Step A: 1-Benzyl-3-(4-methoxyphenyl)piperidin-3-ol

To a solution of 1-benzylpiperidin-3-one (5 g, 26 mmol) in THF (30 mL)was added (4-methoxyphenyl)magnesium bromide (0.5 M in ether) (66 mL, 33mmol) at rt under a nitrogen atmosphere. The reaction was stirred for 2h and then diluted with sat. ammonium chloride solution and extractedwith ethyl acetate (200 mL). The organic layer was dried over Na2SO4 andevaporated under reduced pressure to give crude1-benzyl-3-(4-methoxyphenyl)piperidin-3-ol (5.1 g, 10.29 mmol, 38.9%yield) with was used in the next step without further purification. LCMS(Method 107): (ES-API), m/z 298.2 (M+H) RT=1.703 min.

Step B: 1-Benzyl-5-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine

To a solution of 1-benzyl-3-(4-methoxyphenyl)piperidin-3-ol (3.5 g, 11.8mmol) in dioxane (20 mL) was added concentrated HCl (3.6 mL, 43 mmol)and the reaction mixture was stirred overnight. The solvents wereevaporated under reduced pressure and the residue was diluted with sat.bicarbonate solution (200 mL) and extracted with ethyl acetate (200 mL).The organic layer was dried over Na₂SO₄ and evaporated under reducedpressure to give the crude product which was purified via silica gelchromatography eluting with 30% ethyl acetate in hexane to give1-benzyl-5-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (1.5 g, 4.2mmol, 35.6% yield). LCMS (Method 107): (ES-API), m/z 280.2 (M+H)RT=2.263 min; ¹H NMR (300 MHz, DMSO-d₆) δ 7.42-7.32 (m, 4H), 7.29-7.19(m, 3H), 6.91-6.82 (m, 2H), 6.16-5.97 (m, 1H), 3.73 (s, 3H), 3.65 (d,J=2.6 Hz, 3H), 3.23 (d, J=1.9 Hz, 2H), 2.55 (s, 1H), 2.24 (d, J=3.8 Hz,2H).

Step C: 3-(4-Methoxyphenyl)piperidine

To a solution of 1-benzyl-5-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine(1.5 g, 5.4 mmol) in 50 mL of methanol was added 10% Pd/C (1.14 g).Hydrogen gas was introduced via balloon and the reaction mixture wasstirred overnight at rt. The reaction mixture was then filtered throughCelite, and the filter pad was washed with additional methanol (100 mL).The filtrates were combined, and the methanol was evaporated underreduced pressure to give 3-(4-methoxyphenyl)piperidine (950 mg, 3.73mmol, 69.4% yield). LCMS (Method 107): (ES-API), m/z 192.2 (M+H)RT=1.497 min; ¹H NMR (300 MHz, DMSO-d6) δ 7.13 (dt, J=8.5, 2.0 Hz, 2H),6.84 (dt, J=8.5, 2.2 Hz, 2H), 3.72 (s, 3H), 3.17 (s, 2H), 2.93 (d,J=10.6 Hz, 2H), 2.49-2.39 (m, 1H), 1.81 (d, J=1.9 Hz, 1H), 1.74-1.57 (m,1H), 1.57-1.40 (m, 2H).

Intermediate 26 3-(4-Methoxyphenyl)azetidine Step A. tert-Butyl3-hydroxy-3-(4-methoxyphenyl)azetidine-1-carboxylate

To a solution of tert-butyl 3-oxoazetidine-1-carboxylate (4 g, 23 mmol)in THF (100 mL) at 0° C. was added (4-methoxyphenyl)magnesium bromide(0.5 M in ether) (47 mL, 23 mmol). The reaction mixture was stirred for3 h, and then a satd. ammonium chloride solution (200 mL) was added. Themixture was extracted with ethyl acetate (200 mL), and the organic layerwas separated, dried over Na2SO4, and evaporated under reduced pressureto give a crude product. The product was purified by silica gelchromatography eluting with 25% ethyl acetate in hexane to givetert-butyl 3-hydroxy-3-(4-methoxyphenyl)azetidine-1-carboxylate (2.2 g,7.64 mmol, 32.7% yield). LCMS (Method 107): m/z 280.7 (M+H) RT=1.929min; ¹H NMR (400 MHz, DMSO-d₆) δ 7.39 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.8Hz, 2H), 6.21 (s, 1H), 4.00 (s, 3H), 3.75 (s, 3H), 1.41 (s, 9H).

Step B tert-Butyl 3-(4-methoxyphenyl)azetidine-1-carboxylate

To a solution of tert-butyl3-hydroxy-3-(4-methoxyphenyl)azetidine-1-carboxylate (1.1 g, 3.9 mmol)in DCM (15 mL) at 0° C. was added triethylsilane (5 mL, 31 mmol)followed by TFA (1 mL, 13.8 mmol). The reaction mixture was allowed towarm to rt and stirred overnight. The mixture was then diluted with asatd. sodium bicarbonate solution and extracted with DCM (100 mL). Theorganic layer was separated, dried over Na₂SO₄, filtered, and evaporatedunder reduced pressure to give a crude product which was purified bysilica gel chromatography eluting with 10% ethyl acetate in hexane togive pure tert-butyl 3-(4-methoxyphenyl)azetidine-1-carboxylate (380 mg,1.37 mmol, 34.8% yield). LCMS (Method 107): (ES-API), m/z 264.0 (M+H)RT=2.128 min; ¹H NMR (400 MHz, DMSO-d₆) δ 7.31-7.20 (m, 2H), 6.96-6.87(m, 2H), 4.27-4.17 (m, 2H), 3.82-3.69 (m, 6H), 1.41 (s, 9H).

Step C 3-(4-Methoxyphenyl)azetidine

To a solution of tert-butyl 3-(4-methoxyphenyl)azetidine-1-carboxylate(380 mg, 1.4 mmol) in methanol (10 mL) was added conc HCl (0.44 mL, 5.2mmol) and the reaction mixture was stirred at rt for 3 h. The solventswere removed by evaporation under reduced pressure and the solid residuewas washed with diethyl ether three times (3×10 mL) and then dried underreduced pressure to give 3-(4-methoxyphenyl)azetidine, HCl (125 mg, 0.6mmol, 41% yield). LCMS (Method 107): (ES-API), m/z 164.0 (M+H) RT=1.386min; ¹H NMR (400 MHz, DMSO-d₆) δ 9.39 (br. s., 1H), 9.12 (br. s., 1H),7.37 (dt, J=8.5, 2.5 Hz, 2H), 6.96 (dt, J=8.5, 2.5 Hz, 2H), 4.31-4.13(m, 2H), 4.12-3.89 (m, 3H), 3.76 (s, 3H).

Intermediate 27. 4-(4-Methoxy-2-methylphenyl)piperidine, HCl Step A.tert-Butyl4-hydroxy-4-(4-methoxy-2-methylphenyl)piperidine-1-carboxylate

A solution of tert-butyl 4-oxopiperidine-1-carboxylate (2 g, 10 mmol) indiethyl ether (100 mL) was chilled to 0° C., and a solution of(4-methoxy-3-methylphenyl)magnesium bromide (0.5 M in ether) (20 mL, 10mmol) was added.

The reaction mixture was allowed to warm to rt and stirred for 12 h. Thereaction mixture was then quenched with a saturated NH₄Cl solution andthe mixture was diluted with ethyl acetate. The organic layer wasseparated, washed with brine, dried over anhydrous Na₂SO₄, and thenevaporated under reduced pressure to provide the desired product (2.3 g,71%); ¹H NMR (400 MHz, DMSO-d₆) δ 7.27 (d, J=8.0 Hz, 1H), 6.75-6.61 (m,2H), 4.83 (s, 1H), 3.85-3.77 (m, 2H), 3.71 (s, 3H), 3.17 (d, J=5.0 Hz,2H), 2.51 (s, 3H), 1.82-1.73 (m, 4H), 1.41 (s, 9H).

Step B. 4-(4-Methoxy-2-methylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

A solution of tert-butyl4-hydroxy-4-(4-methoxy-2-methylphenyl)piperidine-1-carboxylate (2.3 g,7.2 mmol) in 1,4-dioxane (20 mL) was chilled to 0° C. and treated with asolution of HCl in dioxane (4.0 M, 1.8 mL, 7.2 mmol). The reactionmixture was stirred at rt for 12 h, and then the solvents wereevaporated to provide a crude compound which was triturated with diethylether to provide the desired product as a solid (1.2 g, 82%). LC/MS(Method P) RT=0.63 min. (M+H)⁺=204.0; ¹H NMR (300 MHz, DMSO-d₆) δ9.51-9.09 (m, 2H), 7.00 (d, J=8.3 Hz, 1H), 6.79-6.71 (m, 2H), 5.52 (t,J=1.5 Hz, 1H), 3.73 (s, 3H), 3.67 (br. s., 2H), 3.26 (d, J=4.5 Hz, 2H),2.45 (d, J=1.9 Hz, 2H), 2.25 (s, 3H)

Step C. 4-(4-Methoxy-2-methylphenyl)piperidine, HCl

To a solution of 4-(4-methoxy-2-methylphenyl)-1,2,3,6-tetrahydropyridine(500 mg, 2.5 mmol) in MeOH (20 mL) was added 10% Pd/C (524 mg). Hydrogengas was introduced under balloon pressure and the reaction mixture wasstirred vigorously for 12 h. The reaction mixture was filtered through aglass fiber filter cartridge, and the filter pad was washed with ethylacetate. The combined organic layers were evaporated under reducedpressure to give 4-(4-methoxy-2-methylphenyl)piperidine, hydrochloride(500 mg, 87% yield). LC/MS (Method P) RT=0.63 min. (M+H)⁺=206.1; ¹H NMR(400 MHz, DMSO-d₆) δ 9.21-8.25 (m, 2H), 7.05 (d, J=8.0 Hz, 1H),6.78-6.71 (m, 2H), 3.71 (s, 3H), 3.30 (d, J=12.0 Hz, 2H), 3.02-2.86 (m,3H), 2.29 (s, 3H), 1.87-1.65 (m, 4H).

Intermediate 28. 4-(3-Fluoro-4-methoxyphenyl)piperidine hydrochlorideStep A. tert-Butyl4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate

To a solution of 4-bromo-2-fluoro-1-methoxybenzene (2 g, 9.7 mmol) intetrahydrofuran (100 mL) at −78° C. was added a solution ofn-butyllithium (1.6 M in hexanes, 7.9 mL, 12.7 mmol). The reactionmixture was stirred in the cold for 2 h, and then a solution oftert-butyl 4-oxopiperidine-1-carboxylate (1.94 g, 9.7 mmol) in THF (10mL) was added dropwise. The mixture was then allowed to warm to rt andstir for 12 h. It was quenched with a saturated NH₄Cl solution anddiluted with ethyl acetate. The organic layer was separated, washed withbrine, dried over anhydrous Na₂SO₄, filtered, and evaporated underreduced pressure. The crude product was purified by silica gelchromatography to provide 2.0 g (63%) of the desired compound; ¹H NMR(400 MHz, DMSO-d₆) δ 7.29 (dd, J=13.3, 2.3 Hz, 1H), 7.24-7.18 (m, 1H),7.10 (t, J=8.0 Hz, 1H), 5.09 (s, 1H), 3.85 (br. s., 2H), 3.82 (s, 3H),1.86-1.68 (m, 2H), 1.56 (d, J=12.0 Hz, 3H), 1.46-1.38 (m, 11H).

Step B. 4-(3-Fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

A solution of tert-butyl4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate (0.5 g,1.5 mmol) in 1,4-dioxane (20 mL) was chilled to 0° C. and treated with asolution of HCl in 1,4 dioxane (4.0 M, 10 mL, 40 mmol). The reactionmixture was stirred at rt for 12 h, and then the solvents were removedto provide a crude compound which was triturated with diethyl ether toprovide the desired product as a solid (1.2 g, 82%). LC/MS (Method 109)RT=1.798 min. (M+H)⁺=207.8; ¹H NMR (300 MHz, DMSO-d₆) δ 9.51-9.09 (m,2H), 7.00 (d, J=8.3 Hz, 1H), 6.79-6.71 (m, 2H), 5.52 (t, J=1.5 Hz, 1H),3.73 (s, 3H), 3.67 (br. s., 2H), 3.26 (d, J=4.5 Hz, 2H), 2.45 (d, J=1.9Hz, 2H), 2.25 (s, 3H)

Step C. 4-(3-Fluoro-4-methoxyphenyl)piperidine hydrochloride

To a solution of 4-(3-fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine(300 mg, 1.4 mmol) in MeOH (10 mL) was added Pd/C (154 mg). Hydrogen gaswas introduced under balloon pressure and the reaction mixture wasstirred vigorously for 12 h. The reaction mixture was filtered through aglass fiber filter cartridge, and the filter pad was washed with ethylacetate. The combined organic layers were evaporated under reducedpressure to give 4-(4-methoxy-2-methylphenyl)piperidine (500 mg, 87%yield). LC/MS (Method P) RT=0.60 min. (M+H)⁺=210.1.

Racemic 1-benzyl-3((4-methoxyphenyl)cycloalkylamino)pyrrolidin-2-ones

Racemic 1-benzyl-3((4-methoxyphenyl)cycloalkylamino)pyrrolidin-2-onesand -piperidones were synthesized by condensing the lactams from Table Iwith cyclic amines 21-28 in the presence of a hindered amine base. Arepresentative procedure follows:

Intermediate A:1-Benzyl-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one

A solution of 3-bromo-1-benzyl-pyrrolidin-2-one (1.4 g, 5.1mmol)(intermediate 3), 4-(4-methoxyphenyl)-piperidine (0.98 g, 5.1 mmol)and DIPEA (3.6 mL, 20.6 mmol) in acetonitrile (15 mL) was heated at 90°C. for 18 h. The reaction mixture was concentrated and the residue wasdissolved in ethyl acetate (150 mL), washed with water and brine, anddried over sodium sulfate. The organic layer was concentrated to yield2.1 g of crude product, which was purified by flash chromatography onsilica gel (24 g) using 100% EtOAc to yield1-benzyl-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one (1.4 g,71%). 1H NMR: 400 MHz, DMSO-d6: δ ppm 1.51-1.65 (m, 2H) 1.66-1.77 (m,2H) 1.86-1.98 (m, 1H) 2.02-2.12 (m, 1H) 2.27-2.45 (m, 2H) 2.66-2.83 (m,2H) 2.99-3.23 (m, 3H) 3.45-3.54 (m, 1H) 3.72 (s, 3H) 4.29-4.46 (m, 2H)6.85 (d, J=9.04 Hz, 2H) 7.16 (d, J=9.04 Hz, 2H) 7.19-7.24 (m, 2H) 7.28(s, 1H) 7.32-7.39 (m, 2H). LCMS: R.T. 1.76 min. LCMS (ES-API), 365.2 m/z(M+H).

Intermediate B:1-Benzyl-3-(3-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one

By a procedure analogous to the synthesis of1-benzyl-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one,1-benzyl-3-(3-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one wasobtained from intermediate 3 and amine 25 (1.4 g, 71%). 1H NMR: 400 MHz,DMSO-d6: δ ppm 1.40 (br. s., 1H) 1.47-1.61 (m, 1H) 1.63-1.82 (m, 2H)1.90-1.96 (m, 1H) 2.00-2.11 (m, 1H) 2.20 (s, 1H) 2.61 (br. s., 3H)2.88-2.96 (m, 1H) 3.05-3.18 (m, 2H) 3.48 (d, J=2.01 Hz, 2H) 3.72 (d,J=1.00 Hz, 3H) 4.25-4.45 (m, 2H) 6.82-6.89 (m, 2H) 7.11-7.22 (m, 4H)7.24-7.35 (m, 3H). LCMS: R.T. 1.75-1.76 min. LCMS (ES-API), 365.2 m/z(M+H).

The intermediates C-AJ in Table 2 were prepared by combining1-benzyl-3-bromo-pyrrolidin-2-ones and -piperidin-2-ones from Table 1with amines 21-28.

TABLE 2 Racemic1-benzyl-3((4-methoxyphenyl)cycloalkylamino)pyrrolidin-2- ones LCMS R.T.LCMS Ion Int. No. Structure (min) (M + H) C

1.02 399.0 D

1.11 397.2 E

1.04 383.2 F

1.92 379.2 G

2.03 393.2 H

2.53 393.2 I

2.42 351.2 J

0.82 417.0 K

0.84 413.0 L

0.93 337.2 M

1.10 379.0 N

1.99 401.0 O

2.04 399.0 P

2.04 431.0 Q

2.01 373.0 R

1.98 355.0 S

1.02 379.2 T

1.0 383.2 U

0.77 379.2 V

1.09 397.2 W

0.83 379.1 X

0.81 379.1 Y

0.81 391.2 Z

0.79 393.2 AA

0.78 397.2 AB

0.81 393.2 AC

0.77 379.2 AD

1.08 393.6 AE

1.12 411.3 AF

0.79 379.6 AG

1.15 413.2 AH

1.89 399.1 AI

1.03 369.2 AJ

1.04 383.2

Final compounds were prepared via cleavage of the methoxy group ofintermediates A-AJ using boron tribromide, followed in some cases bychiral chromatography to separate the individual enantiomers.

Example 11-(4-Fluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

To a solution of1-(4-fluorobenzyl)-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one(AJ) (3 g, 7.9 mmol) in dry dichloromethane (100 mL) under a N₂atmosphere at −78° C. was added 1 M boron tribromide in dichloromethane(39 mL, 39 mmol) and the resulting mixture was allowed to warm up toroom temperature over 3 h, with stirring. The reaction was quenched withwater (30 mL) and the organic layer was separated, washed with water andbrine, and concentrated. The crude product was purified by flashchromatography on silica gel using 15% EtOAc in petroleum ether to yieldracemic1-(4-fluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(2.1 g, 73%); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49-1.74 (m, 4H)1.90-2.11 (m, 2H) 2.24-2.42 (m, 2H) 2.65-2.80 (m, 2H) 2.99-3.23 (m, 3H)3.40-3.54 (m, 1H) 4.27-4.46 (m, 2H) 6.61-6.70 (m, 2H) 6.95-7.04 (m, 2H)7.17-7.31 (m, 4H) 9.10-9.16 (m, 1H). LCMS: R.T. 0.880 min. LCMS(ES-API), 369.2 m/z (M+H). A portion of the racemate (40 mg) wasseparated via SFC on a Chiralpak-IA 250 mm×4.6 mm, 5 micron columneluting with 35% solvent B, where solvent A=CO₂ and solvent B=0.3% DEAin methanol at a total flow of 3 mL/min. Peak 1 showed a RT of 4.35 minand Peak 2 showed a RT of 6.29 min.

Example 2a(S)-1-(4-Fluorobenzyl)-3-(4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one

First eluting enantiomer, Peak 1, from the chiral separation ofExample 1. Yield 11 mg. LC/MS RT=1.275 min. (M+H)+=369.2; ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.47-1.59 (m, 1H) 1.65-1.75 (m, 1H) 1.84-1.96 (m,1H) 2.03-2.12 (m, 1H) 2.24-2.43 (m, 1H) 2.63-2.72 (m, 2H) 2.72-2.85 (m,2H) 2.96-3.05 (m, 2H) 3.09-3.23 (m, 2H) 3.41-3.54 (m, 1H) 4.23-4.50 (m,2H) 6.58-6.71 (m, 2H) 6.96-7.10 (m, 2H) 7.15-7.21 (m, 2H) 7.26-7.34 (m,2H) 9.06-9.19 (m, 1H).

Example 2b(R)-1-(4-Fluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Second eluting enantiomer, Peak 2, from the chiral separation ofExample 1. Yield 13 mg. LC/MS RT=1.277 min. (M+H)⁺=369.2; ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.47-1.59 (m, 1H) 1.65-1.75 (m, 1H) 1.84-1.96 (m,1H) 2.03-2.12 (m, 1H) 2.24-2.43 (m, 1H) 2.63-2.72 (m, 2H) 2.72-2.85 (m,2H) 2.96-3.05 (m, 2H) 3.09-3.23 (m, 2H) 3.41-3.54 (m, 1H) 4.23-4.50 (m,2H) 6.58-6.71 (m, 2H) 6.96-7.10 (m, 2H) 7.15-7.21 (m, 2H) 7.26-7.34 (m,2H) 9.06-9.19 (m, 1H).

Example 31-(4-Methylbenzyl)-3-(3-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Intermediate M (110 mg) was deprotected using the conditions in Example1 to yield 103 mg product. LC/MS RT=1.48, 1.51 min. (M+H)⁺=365; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.59-2.04 (m, 4H) 2.28 (d, J=5.52 Hz, 5H)2.90-3.05 (m, 2H) 3.17 (s, 3H) 3.26 (d, J=6.53 Hz, 4H) 3.65-3.80 (m, 2H)4.39 (d, J=3.01 Hz, 3H) 6.75 (d, J=8.53 Hz, 2H) 7.02-7.20 (m, 6H)9.35-9.45 (m, 1H) 10.34-10.54 (m, 1H).

Example 41-(4-Fluorobenzyl)-3-(3-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Intermediate E (150 mg) was deprotected using the conditions in Example1 to yield 80 mg product. LC/MS (Method N) RT=1.30, 1.41 min.(M+H)⁺=369. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27-1.39 (m, 1H) 1.47-1.56(m, 1H) 1.68-1.82 (m, 1H) 1.86-1.96 (m, 1H) 2.00-2.08 (m, 1H) 2.10-2.22(m, 1H) 2.30-2.37 (m, 1H) 2.53-2.60 (m, 1H) 2.61-2.74 (m, 1H) 2.85-2.94(m, 1H) 3.07-3.15 (m, 1H) 3.40-3.50 (m, 1H) 4.21-4.46 (m, 2H) 6.66-6.73(m, 2H) 6.97-7.04 (m, 1H) 7.06-7.18 (m, 2H) 7.20-7.27 (m, 2H) 9.08-9.16(m, 1H).

Example 51-(3,4-Difluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Intermediate N (150 mg) was deprotected using the conditions in Example1 to yield 23 mg product. LC/MS RT=1.474 min. (M+H)⁺=367; ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.59-2.04 (m, 4H) 2.28 (d, J=5.52 Hz, 5H) 2.90-3.05(m, 2H) 3.17 (s, 3H) 3.26 (d, J=6.53 Hz, 4H) 3.65-3.80 (m, 2H) 4.39 (d,J=3.01 Hz, 3H) 6.75 (d, J=8.53 Hz, 2H) 7.02-7.20 (m, 6H) 9.35-9.45 (m,1H) 10.34-10.54 (m, 1H). A portion of the racemate (20 mg) was separatedvia SFC on a Chiralpak-AD H 250 mm×4.6 mm, 5 micron column eluting with35% solvent B, where solvent A=CO₂ and solvent B=0.3% DEA in methanol ata total flow of 3 mL/min. Peak 1 showed a RT of 3.50 min and Peak 2showed a RT of 7.17 min.

Example 6a(S)-1-(3,4-Difluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

First eluting enantiomer, Peak 1, from the chiral separation of Example5. Yield 1.5 mg. LC/MS RT=2.107 min. (M+H)⁺=387; ¹H NMR (400 MHz, CD₃OD)δ ppm 1.69-1.85 (m, 4H) 2.03-2.26 (m, 2H) 2.38-2.50 (m, 2H) 2.73-2.80(m, 1H) 2.90 (d, J=11.04 Hz, 1H) 3.15-3.21 (m, 1H) 3.23-3.31 (m, 2H)3.64 (t, J=8.78 Hz, 1H) 4.40-4.56 (m, 2H) 6.68-6.77 (m, 2H) 7.03-7.13(m, 3H) 7.18-7.30 (m, 2H).

Example 6b(R)-1-(3,4-Difluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Second eluting enantiomer, Peak 2, from the chiral separation of Example5. Yield 1.8 mg. LC/MS RT=2.107 min. (M+H)⁺=387; ¹H NMR (400 MHz, CD₃OD)δ ppm 1.71-1.86 (m, 5H) 2.05-2.26 (m, 3H) 2.46 (td, J=10.67, 4.77 Hz,3H) 2.75 (td, J=11.04, 3.51 Hz, 2H) 2.85-3.00 (m, 2H) 3.15-3.25 (m, 2H)3.23-3.31 (m, 2H) 3.63-3.70 (m, 1H) 4.38-4.56 (m, 3H) 6.68-6.78 (m, 3H)7.03-7.13 (m, 4H) 7.20-7.32 (m, 3H).

Example 71-(4-(Difluoromethoxy)benzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Intermediate P (209 mg) was deprotected using the conditions in Example1 to yield 33 mg product. LC/MS RT=1.474 min. (M+H)⁺=417; ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.49-1.64 (m, 2H) 1.63-1.73 (m, 2H) 1.88-1.96 (m,1H) 1.99-2.09 (m, 1H) 2.26-2.39 (m, 2H) 2.63-2.85 (m, 2H) 3.00-3.05 (m,1H) 3.14 (d, J=8.03 Hz, 2H) 3.47 (s, 1H) 4.37 (d, J=18.07 Hz, 2H)6.63-6.72 (m, 2H) 6.97-7.38 (m, 7H) 9.11 (s, 1H).

Example 81-(4-Fluorobenzyl)-3-(3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Intermediate AH (250 mg) was deprotected using the conditions in Example1 to yield 36.8 mg product. LC/MS RT=0.815, 0.830 min. (M+H)⁺=385; ¹HNMR (400 MHz, DMSO-d6) δ ppm 1.51-1.68 (m, 2H) 1.86-1.96 (m, 1H)2.01-2.11 (m, 1H) 2.13-2.24 (m, 1H) 2.34-2.43 (m, 0H) 2.54-2.73 (m, 1H)2.83-2.95 (m, 1H) 3.17 (s, 5H) 3.40-3.55 (m, 3H) 4.35 (s, 3H) 6.66 (d,J=8.53 Hz, 2H) 7.01 (d, J=8.53 Hz, 2H) 7.17 (d, J=1.51 Hz, 2H) 7.26 (d,J=5.52 Hz, 2H). A portion of the product (31 mg) was separated into theindividual diastereomers via SFC on a Chiralpak-AS H 250 mm×4.6 mm, 5micron column eluting with 30% solvent B, where solvent A=CO₂ andsolvent B=0.3% DEA in methanol at a total flow of 3 mL/min. Peak 1showed a RT of 3.21 min, Peak 2 showed a RT of 3.76 min, Peak 3 showed aRT of 5.47 min, and Peak 4 showed a RT of 4.38 min.

Example 9a1-(4-Fluorobenzyl)-3-(3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

First eluting diastereomer, Peak 1, from the chiral separation ofExample 8. Yield 4.5 mg. SFC (Method 108) RT=3.21 min. LC/MS RT=1.866min. (M+H)⁺=385; ¹H NMR (400 MHz, CD₃OD) δ 7.29-7.33 (m, 2H), 7.07-7.12(m, 4H), 6.75 (d, J=8.40 Hz, 2H), 4.41 (d, J=14.80 Hz, 1H), 4.53 (d,J=14.80 Hz, 1H), 3.77-3.78 (m, 1H), 3.65-3.70 (m, 1H), 3.25-3.31 (m,3H), 2.78 (q, J=7.20 Hz, 2H), 2.23-2.30 (m, 3H), 2.09 (q, J=8.40 Hz,1H), 1.75-1.78 (m, 2H).

Example 9b1-(4-Fluorobenzyl)-3-(3-hydroxy-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one

Second eluting diastereomer, Peak 2, from the chiral separation ofExample 8. Yield 3.8 mg. SFC (Method 108) RT=3.76 min. LC/MS RT=1.872min. (M+H)⁺=385; ¹H NMR 400 MHz (CD₃OD) δ 7.28-7.31 (m, 2H), 7.05-7.10(m, 4H), 6.73 (d, J=8.40 Hz, 2H), 4.51 (d, J=14.80 Hz, 1H), 4.39 (d,J=14.40 Hz, 1H), 3.75-3.76 (m, 1H), 3.64-3.68 (m, 1H), 3.23-3.28 (m,3H), 2.88 (q, J=7.20 Hz, 1H), 2.75 (s, 1H), 2.20-2.32 (m, 3H), 1.74-1.76(m, 1H).

Example 9c1-(4-Fluorobenzyl)-3-(3-hydroxy-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one

Third eluting diastereomer, Peak 3, from the chiral separation ofExample 8. Yield 3.3 mg. SFC (Method 108) RT=5.47 min. LC/MS RT=1.866min. (M+H)⁺=385; ¹H NMR (400 MHz, CD3OD) δ 7.30-7.33 (m, 2H), 7.07-7.12(m, 4H), 6.75 (d, J=8.40 Hz, 2H), 4.54 (d, J=14.80 Hz, 1H), 4.42 (d,J=14.80 Hz, 1H), 3.77 (q, J=4.40 Hz, 1H), 3.67-3.72 (m, 1H), 3.25-3.34(m, 2H), 2.99-3.01 (m, 2H), 2.30-2.49 (m, 3H), 2.07-2.10 (m, 1H),1.77-1.80 (m, 2H).

Example 9d1-(4-Fluorobenzyl)-3-(3-hydroxy-4-(4-hydroxyphenyl-)piperidin-1-yl)pyrrolidin-2-one

Fourth eluting diastereomer, Peak 4, from the chiral separation ofExample 8. Yield 3.0 mg. SFC (Method 108) RT=4.38 min. LC/MS RT=1.869min. (M+H)⁺=385; ¹H NMR (400 MHz, CD₃OD) δ 7.28-7.31 (m, 2H), 7.05-7.10(m, 4H), 6.73 (d, J=8.40 Hz, 2H), 4.52 (d, J=14.80 Hz, 1H), 4.40 (d,J=14.80 Hz, 1H), 3.75 (q, J=4.40 Hz, 1H), 3.68 (t, J=18.00 Hz, 1H),3.23-3.31 (m, 2H), 2.98 (t, J=14.00 Hz, 2H), 2.39-2.47 (m, 2H), 2.29 (q,J=6.40 Hz, 1H), 2.07 (q, J=8.40 Hz, 1H), 1.75-1.79 (m, 2H).

Example 101-(3,4-Difluorobenzyl)-3-(3-(4-hydroxyphenyl)azetidin-1-yl)pyrrolidin-2-one

Intermediate Q (150 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 95 mg product. LC/MS RT=1.245 min. (M+H)⁺=359; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.59-1.71 (m, 1H) 1.99-2.16 (m, 1H)3.08-3.26 (m, 9H) 3.48-3.55 (m, 2H) 3.63-3.73 (m, 2H) 4.36 (d, J=10.04Hz, 2H) 6.70 (d, J=8.53 Hz, 2H) 7.05-7.12 (m, 1H) 7.15 (d, J=8.53 Hz,2H) 7.22-7.33 (m, 1H) 7.37-7.47 (m, 1H) 8.90-9.52 (m, 1H).

Example 111-(4-Fluorobenzyl)-3-(3-(4-hydroxyphenyl)azetidin-1-yl)pyrrolidin-2-one

Intermediate R (160 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 84 mg product. LC/MS RT=1.182 min. (M+H)⁺=341; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.52-1.71 (m, 1H) 1.99-2.13 (m, 1H)3.08-3.27 (m, 6H) 3.47-3.55 (m, 1H) 3.62-3.75 (m, 2H) 4.35 (d, J=11.55Hz, 2H) 6.67-6.77 (m, 2H) 7.11-7.22 (m, 4H) 7.27 (dd, J=8.53, 5.52 Hz,2H) 9.21 (s, 1H).

Example 121-Benzyl-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Intermediate A (1000 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 290 mg product. LC/MS RT=1.394 min. (M+H)+=351. 400MHz, DMSO-d6: δ ppm 1.58-1.72 (m, 4H), 1.91-1.94 (m, 3H), 2.30-2.37 (m,2H), 2.67-2.81 (m, 2H), 3.15-3.31 (m, 4H), 4.39 (q, J=50.00 Hz, 3H),6.68 (d, J=8.40 Hz, 2H), 7.02 (d, J=8.40 Hz, 2H), 7.22-7.38 (m, 8H),9.13 (s, 1H). Most of the product (250 mg) was separated into theindividual enantiomers via SFC on a Chiralpak-IA 250 mm×4.6 mm, 5 microncolumn eluting with 30% solvent B, where solvent A=CO₂ and solventB=0.3% DEA in methanol at a total flow of 3 mL/min. Peak 1 showed a RTof 5.84 min and Peak 2 showed a RT of 8.33 min.

Example 13a(S)-1-Benzyl-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

First eluting enantiomer, Peak 1, from the chiral separation of compound12. Yield 88 mg. LC/MS RT=1.780 min. (M+H)+=351.2; ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.74-1.84 (m, 4H) 2.02-2.12 (m, 1H) 2.15-2.23 (m, 1H)2.47 (td, J=10.79, 4.52 Hz, 2H) 2.76 (td, J=11.04, 3.51 Hz, 1H) 2.90 (d,J=11.04 Hz, 1H) 3.12-3.20 (m, 1H) 3.21-3.29 (m, 2H) 3.64 (t, J=9.04 Hz,1H) 4.38-4.60 (m, 2H) 6.67-6.76 (m, 2H) 7.04-7.09 (m, 2H) 7.25-7.40 (m,5H).

Example 13b(R)-1-Benzyl-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Second eluting enantiomer, Peak 2, from the chiral separation ofcompound 12.

Yield 96 mg. LC/MS RT=1.783 min. (M+H)+=351.2; ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.74-1.86 (m, 4H) 2.02-2.13 (m, 1H) 2.15-2.25 (m, 1H)2.41-2.52 (m, 2H) 2.76 (td, J=11.04, 3.51 Hz, 1H) 2.90 (d, J=11.04 Hz,1H) 3.14-3.30 (m, 2H) 3.64 (t, J=9.04 Hz, 1H) 4.38-4.58 (m, 2H)6.69-6.75 (m, 2H) 7.03-7.09 (m, 2H) 7.25-7.39 (m, 5H).

Example 141-(3-Chloro-4-methylbenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Intermediate K (200 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 2 mg product. LC/MS RT=1.677 min. (M+H)⁺=399.0; ¹HNMR (400 MHz, DMSO-d₆) δ δ ppm 1.51-1.72 (m, 4H) 1.86-1.98 (m, 1H)2.02-2.11 (m, 1H) 2.31 (s, 6H) 2.69-2.81 (m, 2H) 2.99-3.06 (m, 1H)3.10-3.21 (m, 2H) 3.44-3.51 (m, 1H) 4.28-4.41 (m, 2H) 6.63-6.72 (m, 2H)7.01 (s, 2H) 7.07-7.13 (m, 1H) 7.25-7.35 (m, 2H) 9.08-9.15 (m, 1H).

Example 151-(4-Chloro-3-fluorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Intermediate J (200 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 15 mg product. LC/MS RT=1.575 min. (M+H)⁺=403.0; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.50-1.60 (m, 3H) 1.64-1.73 (m, 3H)1.87-1.97 (m, 2H) 2.04-2.13 (m, 2H) 2.28-2.39 (m, 3H) 2.64-2.72 (m, 2H)2.74-2.81 (m, 1H) 3.03 (d, J=11.55 Hz, 2H) 3.12-3.22 (m, 3H) 3.49 (t,J=8.53 Hz, 2H) 4.31-4.48 (m, 3H) 6.64-6.72 (m, 3H) 7.02 (d, J=8.53 Hz,3H) 7.10 (dd, J=8.53, 1.51 Hz, 2H) 7.26 (dd, J=10.04, 2.01 Hz, 2H) 7.57(t, J=8.03 Hz, 2H) 9.12 (br. s., 1H).

Example 16 1-Benzyl-3-(3-(4-hydroxyphenyl)azetidin-1-yl)pyrrolidin-2-one

Intermediate L (150 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 40 mg product. LC/MS RT=1.154 min. (M+H)⁺=323.0; ¹HNMR (400 MHz, DMSO-d6) δ ppm 1.57-1.68 (m, 1H) 2.03-2.12 (m, 1H)3.11-3.25 (m, 4H) 3.51 (t, J=7.37 Hz, 1H) 3.62-3.74 (m, 2H) 4.28-4.44(m, 2H) 6.67-6.74 (m, 2H) 7.13-7.38 (m, 7H) 9.23 (br. s., 1H).

Example 171-(4-Chlorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Intermediate C (150 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 24 mg product. LC/MS RT=1.576 min. (M+H)⁺=385; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.57-1.73 (m, 1H) 2.19-2.33 (m, 2H) 2.62(d, J=7.93 Hz, 4H) 2.77 (d, J=18.51 Hz, 3H) 3.09-3.21 (m, 3H) 3.40-3.46(m, 1H) 4.36 (s, 2H) 6.63-6.77 (m, 2H) 7.00 (d, J=8.69 Hz, 2H) 7.15-7.26(m, 2H) 7.33-7.49 (m, 2H) 9.03-9.34 (m, 1H). The racemic product wasseparated into the individual enantiomers via SFC on a Chiralpak-IA 250mm×4.6 mm, 5 micron column eluting with 30% solvent B, where solventA=CO₂ and solvent B=0.3% DEA in methanol at a total flow of 3 mL/min.Peak 1 showed a RT of 5.94 min and Peak 2 showed a RT of 10.59 min.

Example 18a(S)-1-(4-Chlorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

First eluting enantiomer, Peak 1, from the chiral separation of compound17. Yield 3.9 mg. LC/MS RT=2.315 min. (M+H)+=385.0; ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.68-1.85 (m, 4H) 1.99-2.09 (m, 1H) 2.16-2.24 (m, 1H)2.37-2.50 (m, 2H) 2.70-2.79 (m, 1H) 2.86-2.95 (m, 1H) 3.23-3.32 (m, 3H)3.56-3.66 (m, 1H) 4.37-4.45 (m, 1H) 4.48-4.58 (m, 1H) 6.71 (d, J=8.53Hz, 2H) 7.01-7.13 (m, 2H) 7.20-7.30 (m, 2H) 7.36 (s, 2H).

Example 18b(R)-1-(4-Chlorobenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Second eluting enantiomer, Peak 2, from the chiral separation ofcompound 17.

Yield 4.7 mg. LC/MS RT=2.350 min. (M+H)⁺=385.2; ¹H NMR (400 MHz,methanol-d4) δ ppm 1.68-1.85 (m, 4H) 1.99-2.09 (m, 1H) 2.16-2.24 (m, 1H)2.37-2.50 (m, 2H) 2.70-2.79 (m, 1H) 2.86-2.95 (m, 1H) 3.23-3.32 (m, 3H)3.56-3.66 (m, 1H) 4.37-4.45 (m, 1H) 4.48-4.58 (m, 1H) 6.71 (d, J=8.53Hz, 2H) 7.01-7.13 (m, 2H) 7.20-7.30 (m, 2H) 7.36 (s, 2H).

Example 191-(3-Fluoro-4-methylbenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Intermediate D (120 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 18 mg product. LC/MS RT=1.552 min. (M+H)⁺=383.0; ¹HNMR (300 MHz, DMSO-d₆) δ ppm 1.48-1.92 (m, 4H) 2.21 (d, J=1.13 Hz, 4H)2.27-2.38 (m, 2H) 2.68-2.86 (m, 1H) 2.97-3.18 (m, 2H) 3.41-3.65 (m, 1H)4.21-4.48 (m, 2H) 6.56-6.74 (m, 2H) 6.89-7.11 (m, 4H) 7.21-7.35 (m, 1H).

Example 201-(3-Fluoro-4-methylbenzyl)-3-(3-(4-hydroxyphenyl)azetidin-1-yl)pyrrolidin-2-one

Intermediate A1 (120 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 35 mg product. LC/MS RT=1.400 min. (M+H)+=355.0; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.59-1.68 (m, 1H) 2.02-2.12 (m, 1H) 2.21(d, J=2.01 Hz, 3H) 3.06-3.15 (m, 2H) 3.22-3.33 (m, 2H) 3.51 (s, 2H)3.62-3.76 (m, 3H) 4.33 (d, J=14.56 Hz, 2H) 6.61-6.77 (m, 2H) 6.87-7.02(m, 2H) 7.09-7.21 (m, 2H) 7.25 (s, 1H). A portion of the product (25 mg)was separated into the individual enantiomers via SFC on a Chiralpak-IA250 mm×4.6 mm, 5 micron column eluting with 40% solvent B, where solventA=CO₂ and solvent B=0.3% DEA in methanol at a total flow of 4 mL/min.Peak 1 showed a RT of 1.81 min and Peak 2 showed a RT of 2.38 min.

Example 21a(R)-1-(3-Fluoro-4-methylbenzyl)-3-(3-(4-hydroxyphenyl)azetidin-1-yl)pyrrolidin-2-one

First eluting enantiomer, peak 1, from the chiral separation of Example20. Yield 5.6 mg. LC/MS RT=2.056 min. (M+H)⁺=355.0; ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.65-1.82 (m, 1H) 2.26 (d, J=2.01 Hz, 4H) 3.29 (d,J=16.56 Hz, 1H) 3.43-3.51 (m, 2H) 3.71 (s, 1H) 3.76-3.84 (m, 1H)3.89-4.02 (m, 1H) 4.42 (d, J=17.07 Hz, 2H) 6.65-6.79 (m, 2H) 6.94-7.05(m, 2H) 7.14-7.27 (m, 3H).

Example 21b(S)-1-(3-Fluoro-4-methylbenzyl)-3-(3-(4-hydroxyphenyl)azetidin-1-yl)pyrrolidin-2-one

Second eluting enantiomer, peak 2, from the chiral separation of Example20. Yield 4.1 mg. LC/MS RT=2.043 min. (M+H)⁺=355.0; ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.65-1.82 (m, 1H) 2.26 (d, J=2.01 Hz, 4H) 3.29 (d,J=16.56 Hz, 1H) 3.43-3.51 (m, 2H) 3.71 (s, 1H) 3.76-3.84 (m, 1H)3.89-4.02 (m, 1H) 4.42 (d, J=17.07 Hz, 2H) 6.65-6.79 (m, 2H) 6.94-7.05(m, 2H) 7.14-7.27 (m, 3H).

Example 223-(4-(4-Hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

Intermediate F (1000 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 98 mg product. LC/MS RT=1.544 min. (M+H)⁺=365; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.48-1.81 (m, 4H) 1.84-2.16 (m, 2H) 2.28(s, 5H) 2.60-2.88 (m, 2H) 2.95-3.25 (m, 3H) 3.40-3.55 (m, 1H) 4.21-4.46(m, 2H) 6.62-7.18 (m, 8H) 9.12 (br. s., 1H). The racemate was separatedinto the individual enantiomers via SFC on a Chiralpak-IA 250 mm×4.6 mm,5 micron column eluting with 30% solvent B, where solvent A=CO₂ andsolvent B=0.3% DEA in methanol at a total flow of 3 mL/min. Peak 1showed a RT of 6.67 min and Peak 2 showed a RT of 9.74 min.

Example 23a(S)-3-(4-(4-Hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

First eluting enantiomer, peak 1, from the chiral separation of Example22. Yield 6 mg. LC/MS RT=1.849 min. (M+H)⁺=365.2 1H NMR (400 MHz,methanol-d₄) δ ppm 1.79 (ddd, J=9.91, 6.15, 4.02 Hz, 4H) 1.99-2.13 (m,1H) 2.14-2.23 (m, 1H) 2.33 (s, 3H) 2.46 (d, J=4.02 Hz, 2H) 2.75 (d,J=3.51 Hz, 1H) 2.83-2.93 (m, 1H) 3.10-3.30 (m, 3H) 3.62 (t, J=8.78 Hz,1H) 4.31-4.55 (m, 2H) 6.67-6.77 (m, 2H) 7.02-7.10 (m, 2H) 7.17 (br. s.,0H).

Example 23b(R)-3-(4-(4-Hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

Second eluting enantiomer, peak 2, from the chiral separation of Example22. Yield 34 mg. LC/MS RT=1.841 min. (M+H)⁺=365.2 1H NMR (400 MHz,methanol-d4) δ ppm 1.66-1.84 (m, 4H) 2.01-2.21 (m, 2H) 2.33 (s, 3H)2.36-2.49 (m, 2H) 2.73 (br. s., 1H) 2.86 (br. s., 1H) 3.06-3.28 (m, 3H)3.30-3.33 (m, 1H) 3.60 (s, 1H) 4.30-4.53 (m, 2H) 6.72 (d, J=8.53 Hz, 2H)7.05 (d, J=8.03 Hz, 2H) 7.10-7.22 (m, 4H).

Example 241-(4-Hydroxybenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Step A.1-(4-Methoxybenzyl)-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one

A mixture of1-(4-methoxybenzyl)-3-(4-(4-methoxyphenyl)-5,6-dihydropyridin-1(2H)-yl)pyrrolidin-2-one(G) (400 mg, 1.02 mmol), MeOH (4 ml) and ethanol (8 ml) was flushed withnitrogen, followed by the addition of 10% Pd/C (108 mg).

Then the mixture was stirred overnight at rt and 25 psi hydrogenpressure. The catalyst was removed by filtration through Celite and thefiltrate was concentrated under vacuum. Yield: 400 mg. LCMS (method F)RT 2.36 min, m/z 395.2 (MH⁺).

Step B.1-(4-Hydroxybenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

The product from step A was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 60 mg of the titled compound of Example 24. LC/MSRT=1.012 min. (M+H)⁺=367.0 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.44-1.61 (m,2H) 1.66-1.77 (m, 2H) 1.91 (s, 2H) 1.99-2.09 (m, 1H) 2.23-2.41 (m, 2H)2.60-2.80 (m, 2H) 3.08 (s, 3H) 3.42-3.52 (m, 1H) 3.91 (s, 1H) 4.20-4.34(m, 2H) 6.60-6.77 (m, 4H) 7.02 (d, J=8.03 Hz, 4H) 9.10 (s, 1H) 9.34 (s,1H). A portion of the product (50 mg) was separated into the individualenantiomers via SFC on a Chiralpak-IA 250 mm×4.6 mm, 5 micron columneluting with 30% solvent B, where solvent A=CO₂ and solvent B=0.3% DEAin methanol at a total flow of 3 mL/min. Peak 1 showed a RT of 5.12 minand Peak 2 showed a RT of 6.47 min.

Example 25a(S)-1-(4-Hydroxybenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

First eluting enantiomer, peak 1, from the chiral separation of Example24. Yield 18 mg. LC/MS RT=1.546 min. (M+H)⁺=367.2 ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.66-1.83 (m, 4H) 1.96-2.21 (m, 2H) 2.38-2.51 (m, 2H)2.73 (td, J=11.04, 3.51 Hz, 1H) 2.83-2.95 (m, 1H) 3.08-3.31 (m, 3H) 3.60(t, J=8.78 Hz, 1H) 4.23-4.46 (m, 2H) 6.65-6.82 (m, 4H) 7.00-7.17 (m,4H).

Example 25b(R)-1-(4-Hydroxybenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Second eluting enantiomer, peak 2, from the chiral separation of Example24. Yield 20 mg. LC/MS RT=1.544 min. (M+H)⁺=367.2 ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.66-1.84 (m, 4H) 1.98-2.08 (m, 1H) 2.11-2.21 (m, 1H)2.38-2.49 (m, 2H) 2.74 (td, J=11.04, 3.51 Hz, 1H) 2.89 (d, J=2.01 Hz,1H) 3.08-3.30 (m, 3H) 3.60 (t, J=8.53 Hz, 1H) 4.23-4.35 (m, 1H)4.40-4.48 (m, 1H) 6.67-6.80 (m, 4H) 7.02-7.17 (m, 4H).

Example 261-(3,4-Dimethylbenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Intermediate H (200 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 21 mg product. LC/MS RT=1.669 min. (M+H)⁺=379.0 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.54-1.62 (m, 2H) 1.90 (d, J=13.05 Hz, 3H)2.03-2.13 (m, 1H) 2.65-2.81 (m, 2H) 2.96-3.03 (m, 1H) 3.10 (s, 2H) 3.45(s, 1H) 3.74 (s, 3H) 4.20-4.41 (m, 2H) 4.74 (s, 1H) 6.84-6.95 (m, 2H)7.11-7.24 (m, 3H) 7.26-7.36 (m, 2H) 7.49 (dd, J=8.28, 1.25 Hz, 2H).

Example 273-(3-(4-Hydroxyphenyl)azetidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

Intermediate I (110 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 44 mg product. LC/MS RT=1.341 min. (M+H)⁺=337.0 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.56-1.66 (m, 1H) 2.08 (s, 1H) 2.29 (s, 3H)3.11 (d, J=1.51 Hz, 3H) 3.23 (s, 2H) 3.46-3.53 (m, 1H) 3.61-3.75 (m, 2H)4.31 (d, J=13.05 Hz, 2H) 6.65-6.75 (m, 2H) 7.05-7.20 (m, 6H) 9.19-9.27(m, 1H). A portion of the product (34 mg) was separated into theindividual enantiomers via SFC on a Lux Cellulose 2 250 mm×4.6 mm, 5micron column eluting with 40% solvent B, where solvent A=CO₂ andsolvent B=0.3% DEA in methanol at a total flow of 3 mL/min. Peak 1showed a RT of 4.65 min and Peak 2 showed a RT of 3.54 min.

Example 28a(S)-3-(3-(4-Hydroxyphenyl)azetidin-1-yl)-1-(4-methylbenzyl-)pyrrolidin-2-one

First eluting enantiomer, peak 1, from the chiral separation of Example27. Yield 8 mg. LC/MS RT=1.683 min. (M+H)⁺=337.2 ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.68-1.81 (m, 1H) 2.18-2.24 (m, 1H) 2.33 (s, 4H)3.13-3.30 (m, 2H) 3.47 (s, 2H) 3.66-3.75 (m, 1H) 3.78-3.85 (m, 1H)3.90-4.00 (m, 1H) 4.41 (d, J=7.03 Hz, 2H) 6.76 (d, J=8.53 Hz, 2H)7.08-7.22 (m, 6H).

Example 28b(R)-3-(3-(4-Hydroxyphenyl)azetidin-1-yl)-1-(4-methylbenzyl)-pyrrolidin-2-one

Second eluting enantiomer, peak 2, from the chiral separation of Example27. Yield 6 mg. LC/MS RT=1.683 min. (M+H)+=337.2 ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.71-1.81 (m, 1H) 2.19-2.26 (m, 1H) 2.33 (s, 3H) 3.04(s, 1H) 3.15-3.26 (m, 1H) 3.24 (s, 2H) 3.45-3.58 (m, 2H) 3.68-3.73 (m,1H) 3.78-3.85 (m, 1H) 3.91-4.00 (m, 1H) 4.41 (d, J=7.03 Hz, 2H)6.67-6.80 (m, 2H) 7.10-7.22 (m, 6H).

Example 291-Benzyl-3-(4-(4-hydroxy-2-methylphenyl)piperidin-1-yl)pyrrolidin-2-one

Intermediate S (200 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 30 mg product. LC/MS RT=1.47 min. (M+H)+=365.2 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.47-1.67 (m, 4H) 1.84-1.98 (m, 1H)2.01-2.13 (m, 1H) 2.20 (s, 3H) 2.27-2.39 (m, 1H) 2.67-2.82 (m, 1H)2.99-3.07 (m, 2H) 3.08-3.22 (m, 1H) 3.43-3.54 (m, 2H) 4.29-4.47 (m, 2H)6.53 (s, 2H) 6.95-7.01 (m, 1H) 7.17-7.27 (m, 2H) 7.25-7.32 (m, 1H) 7.35(d, J=7.53 Hz, 2H) 8.98 (s, 1H).

Example 301-Benzyl-3-(4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Intermediate T (200 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 38 mg product. LC/MS RT=1.46 min. (M+H)+=369 ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.47-1.60 (m, 2H) 1.65-1.75 (m, 2H) 1.89-1.97(m, 1H) 2.02-2.13 (m, 1H) 2.23-2.43 (m, 2H) 2.64-2.73 (m, 1H) 2.76-2.82(m, 1H) 2.98-3.06 (m, 1H) 3.09-3.22 (m, 2H) 3.48 (s, 2H) 4.35 (s, 1H)4.28-4.37 (s, 1H) 6.80-6.89 (m, 2H) 6.94-7.03 (m, 1H) 7.17-7.25 (m, 2H)7.25-7.31 (m, 1H) 7.34 (d, J=7.53 Hz, 2H).

Example 311-(4-Fluorobenzyl)-3-(3-(4-hydroxyphenyl)azepan-1-yl)pyrrolidin-2-one

Intermediate V (120 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 19 mg product. LC/MS RT=1.56 min. (M+H)⁺=383; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.48-1.85 (m, 6H) 2.02-2.19 (m, 1H) 2.59-2.84(m, 4H) 2.93-3.12 (m, 3H) 3.51-3.66 (m, 1H) 4.20-4.43 (m, 2H) 6.59-6.72(m, 2H) 6.93-7.03 (m, 2H) 7.05-7.16 (m, 2H) 7.17-7.25 (m, 2H) 8.98-9.15(m, 1H).

Example 323-(4-(4-Hydroxyphenyl)piperidin-1-yl)-1-((S)-1-phenylethyl)pyrrolidin-2-one

Intermediate W (220 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 41 mg product. LC/MS RT=1.45 min. (M+H)⁺=365.2; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 10.00 (q, J=7.20 Hz, 3H), 1.62 (t, J=46.00Hz, 2H), 1.68 (d, J=1.20 Hz, 2H), 1.97-2.19 (m, 1H), 2.22-2.40 (m, 2H),2.78 (t, J=7.60 Hz, 3H), 2.89-3.19 (m, 2H), 3.31 (d, J=3.60 Hz, 1H),3.38-3.45 (m, 2H), 3.47-3.61 (m, 3H), 5.28 (d, J=6.80 Hz, 1H), 6.65-6.68(m, 2H), 6.99-7.02 (m, 2H), 7.25-7.28 (m, 3H), 7.33-7.37 (m, 2H). Aportion of the product (34 mg) was separated into the individualdiastereomers via SFC on a Chiralpak-IA 250 mm×4.6 mm, 5 micron columneluting with 40% solvent B, where solvent A=CO₂ and solvent B=0.3% DEAin methanol at a total flow of 4 mL/min. Peak 1 showed a RT of 2.70 minand Peak 2 showed a RT of 4.03 min.

Example 33a(S)-3-(4-(4-Hydroxyphenyl)piperidin-1-yl)-1-((S)-1-phenylethyl)pyrrolidin-2-one

First eluting diastereomer, peak 1, from the chiral separation ofExample 32. Yield 6 mg. LC/MS RT=2.28 min. (M+H)⁺=365.0; ¹H NMR (400MHz, DMSO-d₆) δ 1.44 (d, J=7.2, 3H), 1.50-1.56 (m, 2H), 1.66 (m, 2H),1.84 (m, 1H), 2.00-2.15 (m, 1H), 2.30-2.33 (m, 2H), 2.66 (m, 1H), 2.74(m, 1H), 2.88-2.95 (m, 1H), 2.95-3.05 (m, 1H), 3.21 (m, 1H), 3.45 (t,J=8.8, 1H), 5.25 (d, J=7.2, 1H), 6.67 (dd, J=2, 6.8, 2H), 7.01 (d,J=8.4, 2H), 7.25-7.29 (m, 3H), 7.34-7.38 (m, 2H), 9.1 (s, 1H).

Example 33b(R)-3-(4-(4-Hydroxyphenyl)piperidin-1-yl)-1-((S)-1-phenylethyl)pyrrolidin-2-one

Second eluting diastereomer, peak 2, from the chiral separation ofExample 32.

Yield 8 mg. LC/MS RT=2.29 min. (M+H)⁺=365.2; ¹H NMR (400 MHz, DMSO-d₆) δppm 1.47 (d, J=7.20 Hz, 3H), 1.51-1.58 (m, 2H), 1.66-1.69 (m, 2H),1.89-2.02 (m, 1H), 2.02-2.19 (m, 1H), 2.29-2.35 (m, 2H), 2.62-2.73 (m,1H), 2.75-2.83 (m, 2H), 2.97-3.15 (m, 1H), 3.60 (t, J=8.80 Hz, 1H),5.28-5.30 (m, 1H), 6.67 (dd, J=2.00, 6.80 Hz, 2H), 7.02 (d, J=8.40 Hz,2H), 7.25-7.29 (m, 3H), 7.34-7.38 (m, 2H), 9.10 (s, 1H).

Example 341-(2,3-Dihydro-1H-inden-1-yl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Intermediate Y (280 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 7 mg product. LC/MS RT=1.52 min. (M+H)⁺=377; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.56-1.59 (m, 2H), 1.69-1.72 (m, 2H), 1.83-2.11(m, 3H), 2.33-2.50 (m, 3H), 2.77-3.04 (m, 6H), 3.11-3.18 (m, 4H), 3.49(t, J=8.40 Hz, 1H), 5.60 (t, J=8.00 Hz, 1H), 6.68 (dd, J=2.00, 6.60 Hz,2H), 7.01-7.04 (m, 3H), 7.20-7.29 (m, 3H).

Example 351-(4-Fluorobenzyl)-3-(4-(4-hydroxyphenyl)azepan-1-yl)pyrrolidin-2-one

Intermediate AA (110 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 25 mg product. LC/MS RT=1.50 min. (M+H)⁺=383; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.67-1.81 (m, 7H), 2.15-2.20 (m, 1H), 2.65-2.70(m, 3H), 2.79-2.92 (m, 2H), 3.09-3.02 (m, 1H), 3.13-3.18 (m, 2H),3.58-3.61 (m, 2H), 4.35 (t, J=3.20 Hz, 2H), 6.65 (dd, J=3.60, 6.40 Hz,2H), 6.97-6.99 (m, 2H), 7.15-7.19 (m, 2H), 7.24-7.28 (m, 2H)

Example 363-(4-(4-Hydroxyphenyl)azepan-1-yl)-1-(4-methylbenzyl)-pyrrolidin-2-one

Intermediate AB (100 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 14 mg product. LC/MS RT=1.60 min. (M+H)+=379.2; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.50-89.00 (m, 7H), 2.13 (s, 1H), 2.28 (s,3H), 2.71 (s, 1H), 2.84 (s, 2H), 3.12 (s, 3H), 3.62 (s, 1H), 4.35 (d,J=14.00 Hz, 2H), 6.66 (d, J=8.00 Hz, 2H), 6.99 (d, J=8.00 Hz, 2H), 7.14(t, J=12.00 Hz, 5H), 9.06 (s, 1H).

Example 37 1-Benzyl-3-(4-(4-hydroxyphenyl)azepan-1-yl)pyrrolidin-2-one

Intermediate AC (90 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield 15 mg product. LC/MS RT=1.44 min. (M+H)+=365.2 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.70-1.85 (m, 8H), 2.19-2.25 (m, 1H),2.66-2.71 (m, 3H), 2.79-2.93 (m, 2H), 2.96-3.15 (m, 1H), 3.14-3.20 (m,3H), 3.61 (t, J=4.00 Hz, 3H), 4.37 (t, J=7.20 Hz, 4H), 6.65 (dd, J=2.00,8.60 Hz, 2H), 6.98 (d, J=8.40 Hz, 2H), 7.20-7.33 (m, 3H), 7.35-7.37 (m,2H).

Example 384-(4-Hydroxyphenyl)-1′-(4-methylbenzyl)-[1,3′-bipiperidin]-2′-one

Step A.4-(4-Methoxyphenyl)-1′-(4-methylbenzyl)-[1,3′-bipiperidin]-2′-one

Intermediate AD (130 mg) was hydrogenated as in Example 24 to yield 130mg 4-(4-methoxyphenyl)-1′-(4-methylbenzyl)-[1,3′-bipiperidin]-2′-one.LCMS (method) RT 1.08 min, m/z 393.6 (MH⁺).

Step B.4-(4-Hydroxyphenyl)-1′-(4-methylbenzyl)-[1,3′-bipiperidin]-2′-one

The intermediate(4-(4-methoxyphenyl)-1′-(4-methylbenzyl)-[1,3′-bipiperidin]-2′-one) (130mg) was deprotected using the conditions in Example 1 to yield a crudeproduct which was purified via preparative HPLC (Method B) to yield 28mg of the titled compound of Example 38. LC/MS RT=1.42 min. (M+H)⁺=379.2¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.79-2.07 (m, 6H) 2.29 (s, 5H) 2.65-2.79(m, 1H) 3.10-3.31 (m, 7H) 4.26-4.37 (m, 1H) 4.46 (s, 1H) 4.57-4.70 (m,1H) 6.73 (d, J=8.53 Hz, 2H) 7.04 (d, J=8.53 Hz, 2H) 7.18 (s, 4H)9.16-9.34 (s, 1H) 9.56-9.72, (s, 1H).

Example 391′-(3-Fluoro-4-methylbenzyl)-4-(4-hydroxyphenyl)-[1,3′-bipiperidin]-2′-one

Step A.1′-(3-Fluoro-4-methylbenzyl)-4-(4-methoxyphenyl)-[1,3′-bipiperidin]-2′-one

Intermediate AE (100 mg) was hydrogenated as in Example 24 to yield ˜100mg crude1′-(3-fluoro-4-methylbenzyl)-4-(4-methoxyphenyl)-[1,3′-bipiperidin]-2′-oneas a 2:1 mixture with unreacted starting material. LCMS (method) RT 1.12min, m/z 411.3 (MH⁺), 1.16 min, m/z 409.2 (MH⁺- H₂).

Step B.1′-(3-Fluoro-4-methylbenzyl)-4-(4-hydroxyphenyl)-[1,3′-bipiperidin]-2′-one

The intermediate1′-(3-fluoro-4-methylbenzyl)-4-(4-methoxyphenyl)-[1,3′-bipiperidin]-2′-one(100 mg) was deprotected using the conditions in Example 1 to yield acrude product which was purified via preparative HPLC (Method B) toyield 25 mg of the titled compound of Example 39. LC/MS RT=1.52 min.(M+H)⁺=399 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40-1.91 (m, 8H) 2.12-2.26(m, 3H) 2.29-2.49 (m, 2H) 2.75-2.93 (m, 2H) 2.98-3.27 (m, 4H) 4.36-4.59(m, 2H) 6.59-6.75 (m, 2H) 6.92-7.07 (m, 4H) 7.19-7.31 (m, 1H) 9.00-9.20(m, 1H).

Example 40 1′-Benzyl-4-(4-hydroxyphenyl)-[1,3′-bipiperidin]-2′-one

Step A. 1′-Benzyl-4-(4-methoxyphenyl)-[1,3′-bipiperidin]-2′-one

Intermediate AF (100 mg) was hydrogenated as in Example 24 to yield ˜100mg crude 1′-benzyl-4-(4-methoxyphenyl)-[1,3′-bipiperidin]-2′-one. LCMS(method) RT 0.79 min, m/z 379.6 (MH⁺)

Step B. 1′-Benzyl-4-(4-hydroxyphenyl)-[1,3′-bipiperidin]-2′-one

The crude crude 1′-benzyl-4-(4-methoxyphenyl)-[1,3′-bipiperidin]-2′-onefrom step A was deprotected as in example 1 to yield a crude productwhich was purified via preparative HPLC (Method B) to yield 75 mg of thetitled compound of Example 40.

LC/MS RT=1.27 min. (M+H)⁺=365.2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.46-1.60 (m, 2H) 1.63-1.90 (m, 5H) 2.31-2.48 (m, 2H) 2.80-2.91 (m, 2H)3.18 (s, 6H) 4.43-4.61 (m, 2H) 6.68 (d, J=8.53 Hz, 2H) 7.02 (d, J=8.53Hz, 2H) 7.21-7.29 (m, 3H) 7.34 (d, J=7.53 Hz, 2H). A portion (63 mg) wasseparated into the separate enantiomers via SFC on a Chiralpak-OD-H 250mm×4.6 mm, 5 micron column eluting with 30% solvent B, where solventA=CO₂ and solvent B=0.3% DEA in methanol at a total flow of 3 mL/min.Peak 1 showed a RT of 4.50 min and Peak 2 showed a RT of 5.86 min.

Example 41a 1′-Benzyl-4-(4-hydroxyphenyl)-[1,3′-bipiperidin]-2′-one

First eluting enantiomer, peak 1, from the chiral separation of Example40. Yield 11 mg. LC/MS RT=1.94 min. (M+H)+=365.2 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.44-1.59 (m, 2H) 1.61-1.73 (m, 3H) 1.85 (s, 3H) 2.50(br. s, 2H) 2.79-2.90 (m, 2H) 3.02-3.29 (m, 3H) 4.47 (s, 1H) 4.54 (s,1H) 6.67 (d, J=8.53 Hz, 2H) 7.02 (d, J=8.53 Hz, 2H) 7.19-7.40 (m, 5H)8.87-9.09 (m, 1H).

Example 41b 1′-Benzyl-4-(4-hydroxyphenyl)-[1,3′-bipiperidin]-2′-one

Second eluting enantiomer, peak 2, from the chiral separation of Example40. Yield 7 mg. LC/MS RT=1.94 min. (M+H)⁺=365.2 1H NMR (300 MHz,DMSO-d6) δ ppm 1.54 (br. s., 2H) 1.65 (d, J=10.95 Hz, 3H) 1.82 (d,J=15.11 Hz, 3H) 2.44 (br. s., 2H) 2.85 (br. s., 2H) 3.02-3.20 (m, 3H)3.25 (dd, J=9.82, 6.04 Hz, 2H) 4.35-4.50 (m, 1H) 4.52-4.67 (m, 1H)6.57-6.72 (m, 2H) 6.94-7.08 (m, 2H) 7.18-7.31 (m, 3H) 7.34-7.36 (2, m),8.89-9.24 (m, 1H).

Example 421′-(4-Chlorobenzyl)-3-(4-hydroxyphenyl)-[1,3′-bipiperidin]-2′-one

Intermediate AG (120 mg) was deprotected using the conditions in Example1 to yield a crude product which was purified via preparative HPLC(Method B) to yield one pair of racemic diastereomers (out of twopossible pairs). Yield 19 mg. LC/MS RT=1.56 min. (M+H)⁺=399 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.60-1.72 (m, 1H) 1.78-1.89 (m, 3H) 1.93-2.08 (m,3H) 2.22-2.36 (m, 1H) 3.05-3.20 (m, 3H) 3.22-3.38 (m, 5H) 4.17-4.31 (m,1H) 4.44-4.54 (m, 1H) 4.58-4.71 (m, 1H) 6.67-6.78 (m, 2H) 7.01-7.14 (m,2H) 7.24-7.38 (m, 2H) 7.34-7.49 (m, 2H) 9.23-9.41 (m, 1H) 9.60-9.76 (m,1H).

Example 43(R)-1-(3,4-Dihydroxybenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Step A. (R)-tert-Butyl(1-((3,4-dimethoxybenzyl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate

To a 0° C. solution of (3,4-dimethoxyphenyl)methanamine (2 g, 12 mmol)in DCM (20 mL) was added sequentially(R)-2-((tert-butoxycarbonyl)amino)-4-(methylthio)butanoic acid (3.28 g,13.2 mmol), PyBOP (6.85 g, 13.2 mmol) and DIPEA (4.18 mL, 23.92 mmol).The reaction mixture was stirred and allowed to warm up to ambienttemperature over 2 h. The reaction was then quenched by the addition ofwater and the mixture was extracted twice with 100 mL DCM. The organicfraction was washed with 50 mL water, 50 mL brine, and the layers wereseparated. The organic fraction was dried over sodium sulfate, filtered,and evaporated. The residue was purified via silica gel chromatography,eluting with 30% ethyl acetate/petroleum ether. Yield 3.5 gms(R)-tert-butyl(1-((3,4-dimethoxybenzyl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate.LCMS (Method F) RT 2.3 min, m/z 399.2 (MH⁺); ¹H NMR (400 MHz,chloroform-d) δ 1.41 (s, 9H), 1.91-1.98 (m, 1H), 2.07 (s, 3H), 2.10-2.14(m, 1H), 2.47-2.61 (m, 2H), 3.65 (s, 6H), 4.25-4.27 (br s, 1H),4.33-4.42 (m, 2H), 5.16 (br s, 1H), 6.47 (br s, 1H), 6.80 (s, 3H).

Step B.(R)-(3-(tert-butoxycarbonylamino)-4-(3,4-dimethoxybenzylamino)-4-oxobutyl)dimethylsulfoniumiodide

A mixture of (R)-tert-butyl(1-((3,4-dimethoxybenzyl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate(2 g, 5 mmol) and methyl iodide (24 ml, 381 mmol) was stirred at RT for48 hrs. The solvent was then evaporated off and the residue wastriturated with ether and dried under high vacuum. Yield 2 g. LCMS(Method J) RT 0.64 min, m/z 413.1 (M+); ¹H NMR (400 MHz, chloroform-d) δ1.40 (s, 9H), 2.08-2.21 (br s, 1H), 2.55-2.70 (br s, 1H), 3.06 (s, 3H),3.23 (s, 3H), 3.70-3.80 (br s, 1H), 3.85 (s, 3H), 3.89 (s, 3H), 4.34 (m,2H), 4.45-4.55 (br s, 1H), 6.07 (d, J=6.8, 1H) 6.79 (d, J=8, 1H), 6.91(m, 1H), 7.26 (s, 1H), 8.16 (s, 1H). The crude reaction product was useddirectly in the next step.

Step C. (R)-tert-Butyl(1-(3,4-dimethoxybenzyl)-2-oxopyrrolidin-3-yl)carbamate

To a 0° C. solution of(R)-(3-((tert-butoxycarbonyl)amino)-4-((3,4-dimethoxybenzyl)amino)-4-oxobutyl)dimethylsulfonium,iodide salt (2 g, 3.7 mmol) in THF (50 mL) was added LHMDS (3.7 mL, 3.7mmol) dropwise. The reaction was stirred at 0° C. for a further 2 hrs.Then was added saturated ammonium chloride solution and water. Themixture was extracted with 100 mL ethyl acetate. The layers wereseparated and the organic fraction was washed with water and brine. Itwas then dried over sodium sulfate, filtered, and evaporated. Theresidue was purified via silica gel chromatography using 50% ethylacetate/petroleum ether.

Yield 0.8 gms (R)-tert-butyl(1-(3,4-dimethoxybenzyl)-2-oxopyrrolidin-3-yl)carbamate. LCMS (method P)RT 0.82 min, m/z 351.2 (MH⁺); ¹H NMR (400 MHz, chloroform-d) δ 1.45 (s,9H), 1.78-1.86 (m, 1H), 2.57-2.60 (br s, 1H), 3.15-3.23 (m, 2H), 3.68(s, 6H), 4.12-4.25 (br s, 1H), 4.40 (m, 2H), 5.14 (br s, 1H), 6.75-6.82(m, 3H).

Step D. (R)-3-Amino-1-(3,4-dimethoxybenzyl)pyrrolidin-2-one

To a 0° C. solution of (R)-tert-butyl(1-(3,4-dimethoxybenzyl)-2-oxopyrrolidin-3-yl)carbamate (0.7 g, 2 mmol)in dioxane (2 mL) was added dropwise HCl (1 mL, 12 mmol). The solutionwas allowed to warm up to RT with stirring over 2 h. It was thenconcentrated under vacuum and the residue was triturated with diethylether.

Yield 400 mg crude (R)-3-amino-1-(3,4-dimethoxybenzyl)-pyrrolidin-2-one.LCMS (Method J) RT 0.5 min, m/z 251.1 (MH⁺), ¹H NMR (400 MHz,chloroform-d) δ 2.48 (br s, 4H), 3.35 (br s, 2H), 3.70 (s, 3H), 3.8-3.95(m, 6H), 4.4 (br s, 3H), 6.76 (br s, 3H), 8.81 (br s, 3H).

Step E.(R)-1-(3,4-Dimethoxybenzyl)-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one

To a solution of (R)-3-amino-1-(3,4-dimethoxybenzyl)pyrrolidin-2-one(0.4 g, 1.6 mmol) in acetonitrile (10 mL) was added2-(4-methoxyphenyl)propane-1,3-diyl dimethanesulfonate (0.8 g, 1.8 mmol)(prepared as in GAG Sulyok et al; J Med Chem 2001, 44, 1938-1950 and NRios-Lombardia et al, J Org Chem 2011, 76, 5709-5718) and DIPEA (0.84mL, 4.8 mmol). The reaction mixture was heated at 100° C. overnight. Themixture was then concentrated in vacuo, diluted with water, andextracted with 100 mL ethyl acetate. The organic layer was washed withwater and brine, then dried over sodium sulfate. The drying agent wasfiltered off, the solvent was removed under vacuum and the residue waspurified via silica gel chromatography using 20% ethyl acetate/pet etherto yield 200 mg(R)-1-(3,4-dimethoxybenzyl)-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one.LCMS (method J) RT 0.71 min, m/z 425.2 (MH⁺), ¹H NMR (300 MHz,chloroform-d) δ 1.82-1.89 (m, 4H), 2.02-2.16 (m, 2H), 2.44-2.51 (m, 2H),2.81 (m, 1H), 2.96 (m, 1H), 3.08-3.23 (m, 3H), 3.62 (m, 1H), 3.80 (s,3H), 3.88 (s, 3H), 3.89 (s, 3H), 4.34 (d, J=14, 1H), 4.51 (d, J=14, 1H),6.81 (s, 3H), 6.84-6.89 (m, 2H), 7.14-7.14 (m, 2H).

Step F.(R)-1-(3,4-Dihydroxybenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

To a 0° C. solution of(R)-1-(3,4-dimethoxybenzyl)-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one(0.03 g, 0.07 mmol) in DCM (5 mL) was added dropwise boron tribromide(0.07 mL, 0.07 mmol). The solution was allowed to warm up to RT withstirring over 3 h. The reaction was then quenched by the addition ofsaturated sodium bicarbonate solution (10 mL). The mixture was thenextracted with DCM (100 mL) and washed with water (50 mL) and brine (50mL). The organic fraction was dried over sodium sulfate, filtered, andconcentrated under vacuum. The residue was subjected to preparative HPLC(method B) to yield 5.6 mg of the titled compound of Example 43, as apale yellow solid. LCMS (method N) RT 0.93 min (99% AP) m/z 383.0 (MH⁺);¹H NMR (400 MHz, DMSO-d₆) ppm 1.45-1.65 (m, 4H), 1.66-1.75 (m, 1H),1.88-1.92 (m, 1H), 2.32-2.36 (m, 2H), 2.67-2.68 (m, 2H), 3.04-3.31 (m,3H), 4.06-4.25 (m, 2H), 6.46-6.49 (m, 1H), 6.60-6.68 (m, 4H), 7.00-7.03(m, 2H), 8.79 (s, 1H), 8.89 (s, 1H), 9.11 (s, 1H).

Example 44 (Enantiomer-1 and Enantiomer-2)1-(4-Fluorobenzyl)-3-(cis-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Step A. (±)-rel-(3S,4R)-tert-butyl4-(4-(benzyloxy)phenyl)-3-(4-nitrobenzoyloxy)piperidine-1-carboxylate

A mixture of diethylazodicarboxylate (12.9 mL, 81 mmol of 40% toluenesolution), triphenyl phosphine (22 mL, 83 mmol), 4-nitrobenzoic acid(6.97 g, 42 mmol) and 200 mL tetrahydrofuran was stirred for 10 minunder an Ar atmosphere. Then was added a solution of tert-butyl4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (Example 56,step D, 8 g, 20.9 mmol) in tetrahydrofuran (100 mL) and the resultingmixture was stirred at rt overnight. It was then diluted with water andextracted twice with 50 mL ethyl acetate. The combined organic fractionswere dried over Na₂SO₄, filtered, and evaporated to dryness. The residuewas purified via silica gel chromatography (750 gm column, eluting with0-50% ethyl acetate/hexane) to yield 6 gms (±)-rel-(3S,4R)-tert-butyl4-(4-(benzyloxy)phenyl)-3-(4-nitrobenzoyloxy)piperidine-1-carboxylate.LCMS (Method F) RT 2.68 min (87% AP), m/z 476.8 (MH⁺-t-butyl).

Step B. (±)-rel-(3S,4R)-tert-butyl4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate

To a suspension of KOH (5.06 g, 90 mmol), water (60 ml) andtetrahydrofuran (200 ml) was added tert-butyl4-(4-(benzyloxy)phenyl)-3-((4-nitrobenzoyl)oxy)piperidine-1-carboxylate(6 g, 11.3 mmol) and the reaction mixture was stirred at roomtemperature overnight. It was then diluted with 200 mL water andextracted twice with 200 mL ethyl acetate. The organic layer was washedwith 1.5 N HCl solution and was then dried over Na₂SO₄, filtered, andevaporated to dryness. The crude product 4 g, (±)-rel-(3S,4R)-tert-butyl4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate), was used inthe next step without further purification. LCMS (method F) RT 2.44 min(95% AP), m/z 382 (M−H) (negative mode); ¹H NMR (300 MHz, DMSO-d₆) δ ppm7.29-7.44 (m, 5H), 7.71 (d, J=8.4, 2H), 6.91 (d, J=8.4, 2H), 5.06 (s,2H), 4.45 (br s, 1H), 3.80-4.20 (m, 2H), 3.70 (br s, 1H), 2.60-3.05 (m,3H), 1.95-2.20 (m, 1H), 1.35 (s, 9H).

Step C. (±)-rel-(3S,4R)-4-(4-(benzyloxy)phenyl)piperidin-3-ol,hydrochloride

To a solution of tert-butyl4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (100 mg, 0.26mmol) in 10 mL diethyl ether was added 4 M HCl in dioxane (1.3 mL, 5.2mmol) and the resulting mixture was stirred at rt overnight.

The solvent was evaporated off and the residue triturated with ether.Yield 80 mg (88%), LCMS (Method J) RT 0.73 min (92% AP), m/z 284.2(MH⁺), ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.30-7.45 (m, 5H), 7.27 (d,J=8.4, 2H), 6.97 (d, J=8.7, 2H), 5.09 (s, 2H), 4.09 (s, 1H), 3.44 (d,J=12.6, 2H), 3.32-3.29 (m, 1H), 3.08-3.20 (m, 1H), 2.95 (d, J=12.6, 1H),2.48-2.58 (m, 1H), 1.82 (d, J=13.2, 1H).

Step D.(±)-rel-3-((3S,4R)-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one

To a mixture of (±)-rel-(3S,4R)-4-(4-(benzyloxy)phenyl)piperidin-3-ol,HCl (260 mg, 0.81 mmol), 3-bromo-1-(4-fluorobenzyl)pyrrolidin-2-one (442mg, 1.63 mmol, Intermediate 3) and DMF (3 mL) was added triethylamine(0.57 mL, 4 mmol) and the reaction mixture was heated in the microwavefor 1 hour at 120° C. The reaction mixture was cooled, diluted withwater, and twice extracted with 20 mL ethyl acetate. The combinedorganic fractions were dried over Na₂SO₄, filtered, and evaporated todryness. The residue was subjected to preparative HPLC (method F),collecting two racemic diastereomers D1 (90 mg) and D2 (100 mg). Therelative stereochemistry of D1 and D2 was not determined. Data for D1(first eluting diastereomer): LCMS (method E) RT 2.90 min, m/z 475(MH⁺), ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.47-7.37 (m, 4H), 7.36-7.25 (m,3H), 7.23-7.15 (m, 4H), 6.93-6.89 (m, 2H), 5.08 (s, 2H), 4.37 (d, J=14.1Hz, 2H), 3.84 (d, J=7.5 Hz, 1H), 3.72-3.66 (m, 1H), 3.49 (s, 1H), 3.16(d, J=19.6 Hz, 2H), 3.07-3.00 (m, 1H), 2.89 (s, 1H), 2.80-2.74 (m, 1H),2.59-2.53 (m, 1H), 2.38-2.30 (m, 1H), 2.19-2.06 (m, 2H), 1.88 (s, 1H),1.53-1.44 (m, 1H). Data for D2 (second eluting diastereomer): LCMS(method E) RT 2.37 min, m/z 475 (MH⁺), ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.47-7.37 (m, 4H), 7.35-7.25 (m, 3H), 7.22-7.16 (m, 4H), 6.93-6.89 (m,2H), 5.08 (s, 2H), 4.44-4.30 (m, 2H), 3.99 (d, J=7.5 Hz, 1H), 3.72 (d,J=7.5 Hz, 1H), 3.51 (t, J=8.5 Hz, 1H), 3.21-3.10 (m, 2H), 2.97-2.92 (m,1H), 2.85-2.80 (m, 2H), 2.54 (br. s., 1H), 2.47 (s, 1H), 2.16-2.06 (m,2H), 1.92 (s, 1H), 1.48-1.42 (m, 1H).

Step E.(±)-rel-1-(4-fluorobenzyl)-3-((3S,4R)-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

A mixture of3-(4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-fluorobenzyl)-pyrrolidin-2-one(D2 from step E, 85 mg, 0.18 mmol), methanol (5 mL), and 38 mg 10% Pd/Cwas stirred in a pressure vessel overnight under 125 psi hydrogenpressure. The catalyst was removed by filtration through Celite and thefiltrate was evaporated to dryness to yield 70 mg of racemic1-(4-fluorobenzyl)-3-(cis-3-hydroxy-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one.LCMS (method J) RT=0.63 (52% AP), 0.66 (31% AP) min, m/z 385.4 (MH⁺); ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.27-7.28 (m, 2H), 7.15-7.19 (m, 2H), 7.06(d, J=8.4, 2H), 6.45 (d, J=8.4, 2H), 4.39 (d, J=15, 1H), 4.32 (d, J=15,1H), 3.74-3.76 (m, 1H), 3.66 (m, 1H), 3.47 (m, 1H), 3.10-3.18 (m, 2H),3.01 (m, 1H), 2.85-2.88 (m, 1H), 2.76 (m, 1H), 2.30-2.40 (m, 1H),2.06-2.11 (m, 2H), 1.80-1.95 (m, 1H), 1.46 (d, J=12, 1H). The completerelative stereochemistry was not determined.

Step F.1-(4-Fluorobenzyl)-3-(cis-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

The product from Step E,1-(4-fluorobenzyl)-3-(3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(70 mg, 0.182 mmol), was separated via SFC (method C-3) into twoenantiomers, Example 44 E-1 (12 mg) and E-2 (10 mg). E-1 was re-purifiedvia preparative HPLC (method B). The absolute configurations were notdetermined. Data for E-1: LCMS (method N) RT 1.34 min (99% AP), m/z385.0 (MH⁺), Chiral SFC (method C-3) RT 3.2 min; ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.59-1.68 (m, 1H) 2.02-2.35 (m, 3H) 2.50-2.70 (m, 2H)2.79-2.91 (m, 2H) 3.04-3.12 (m, 1H) 3.22-3.30 (m, 2H) 3.73 (s, 1H) 3.84(br. s., 1H) 4.39-4.47 (m, 1H) 4.51-4.60 (m, 1H) 6.71-6.77 (m, 2H)7.06-7.18 (m, 4H) 7.32 (dd, J=8.78, 5.27 Hz, 2H). Data for E-2: LCMS(method F) RT 1.97 min (95% AP), m/z 385.0 (MH⁺), Chiral SFC (methodC-3) RT 7.4 min; ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.59-1.68 (m, 1H)2.02-2.35 (m, 3H) 2.50-2.70 (m, 2H) 2.79-2.91 (m, 2H) 3.04-3.12 (m, 1H)3.22-3.30 (m, 2H) 3.73 (s, 1H) 3.84 (br. s., 1H) 4.39-4.47 (m, 1H)4.51-4.60 (m, 1H) 6.71-6.77 (m, 2H) 7.06-7.18 (m, 4H) 7.32 (dd, J=8.78,5.27 Hz, 2H).

Example 45 (Peak-1, Peak-2, Peak-3, Peak-4)(S)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-oneand(R)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

(S)-3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-oneand(R)-3-((3R,4R)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

Step A. tert-butyl4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate

A stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (4.5 g,22.6 mmol) in diethyl ether (100 mL) at 0° C. was treated with asolution of (3-fluoro-4-methoxyphenyl)magnesium bromide (49.7 mL, 24.8mmol, 0.5 M in tetrahydrofuran). The reaction mixture was allowed towarm to rt and was stirred at for 12 h. It was then diluted with 100 mLwater and the layers were separated. The aqueous layer was extractedthree times with 150 mL of ethyl acetate and the combined organic layerswere dried over anhydrous sodium sulfate, filtered, and evaporated. Theresidue was purified by silica gel chromatography (120 g column) elutingwith 30% ethyl acetate in petroleum ether to obtain 6.5 g of tert-butyl4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate as aclear liquid; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.47 (m, 11H)1.52-1.61 (m, 2H) 1.69-1.84 (m, 2H) 3.03-3.22 (m, 2H) 3.77-3.89 (m, 6H)5.09 (s, 1H) 7.10 (s, 1H) 7.17-7.26 (m, 1H) 7.25-7.33 (m, 1H).

Step B. 4-(3-Fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

To a stirred solution of tert-butyl4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate (6.5 g,20 mmol) in 1,4-dioxane (100 mL) at 0° C. was added 50 mL of 1M HCl(dioxane solution) and the mixture was allowed to warm to rt and stirredfor 12 h. The solvent was then removed under reduced pressure. Theresidue was triturated with ethyl acetate to obtain 4.5 g crude4-(3-fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine hydrochloride asa solid which was isolated by filtration and used without furtherpurification. LCMS (Method P) RT 0.57 min, m/z 208 (M+H⁺); ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.37-2.61 (m, 2H), 3.12-3.38 (m, 3H) 3.80-3.94 (m,3H) 3.95-4.12 (m, 2H) 7.10-7.29 (m, 1H) 7.33-7.44 (m, 1H) 7.51 (dd,J=13.05, 2.51 Hz, 1H) 9.27-9.63 (m, 2H).

Step C. tert-Butyl4-(3-fluoro-4-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate

To a stirring solution of4-(3-fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine hydrochloride(4.5 g, 18.5 mmol) and triethylamine (7.7 mL, 55 mmol) in DCM (30 mL) at0° C. was added 5.6 mL (24 mmol) of di-tert-butyl dicarbonate. Themixture was allowed to warm to rt and was stirred for 12 h. It was thendiluted with DCM (100 mL) and water (100 mL) and the layers wereseparated. The aqueous layer was again extracted with DCM and thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and evaporated under reduced pressure to obtain crudetert-butyl4-(3-fluoro-4-methoxyphenyl)-5,6-dihydro-pyridine-1(2H)-carboxylate (6g) as a liquid which was purified using an 80 g silica gel columneluting with 17%-30% ethyl acetate/petroleum ether to obtain 4.5 g ofthe pure product as a liquid. LCMS (Method P) RT=1.21 min, m/z 252(M+H⁺-t-butyl); ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39-1.48 (m, 9H)2.37-2.46 (m, 2H) 3.52 (s, 2H) 3.77-3.89 (m, 3H) 3.95-4.09 (m, 2H)6.07-6.16 (m, 1H) 7.06-7.17 (m, 1H) 7.18-7.24 (m, 1H) 7.26-7.35 (m, 1H).

Step D. (±)-rel-(3S,4S)-tert-butyl4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate

To a suspension of NaBH₄ (0.37 g, 9.8 mmol) in tetrahydrofuran (50 mL)was added BF₃.OEt₂ (1.3 mL, 10 mmol) at 0° C. The reaction mixture waswarmed to rt for 1 h and then re-cooled to 0° C. Tert-butyl4-(3-fluoro-4-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (1 g,3.3 mmol) in tetrahydrofuran (10 mL) was then added. The resultingmixture was allowed to warm to rt over 2 h. It was then re-cooled to 0°C. and water (4 mL), ethanol (4 mL), 30% H₂O₂ (3 mL, 29.4 mmol) and aNaOH solution (4 mL, 3.25 mmol) were added sequentially and the finalmixture was heated to 65° C. for 12 h. It was cooled to roomtemperature, and 50 mL water and 200 mL ethyl acetate were added. Thelayers were separated and the aqueous layer was twice extracted with 150mL of ethyl acetate. The combined organic layers were washed with 1N HClfollowed by brine. The organic layer was dried over anhydrous Na₂SO₄,filtered, and evaporated under reduced pressure to obtain 2 g of crude(±)-rel-(3S,4S)-tert-butyl4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate as abrown gum. The crude compound was purified on a 40 g silica gel columneluting with 30% ethyl acetate in petroleum ether to obtain 450 mg ofthe pure product as a liquid. LCMS (Method P) RT 0.98 min, m/z 252(M+H⁺-t-butyl), 270 (M+H⁺-t-butyl, —H₂O); ¹H NMR (400 MHz, DMSO-d₆) δppm 1.42 (s, 9H) 1.46-1.58 (m, 1H) 1.61-1.71 (m, 1H) 2.32-2.48 (m, 2H)2.62-2.77 (m, 1H) 3.34-3.47 (m, 1H) 3.80 (s, 3H) 3.91-4.01 (m, 1H)4.05-4.14 (m, 1H) 4.82 (s, 1H) 6.96-7.02 (m, 1H) 7.03-7.13 (m, 2H).

Step E. (±)-rel-(3S,4S)-tert-butyl3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate

A stirred solution of trans-tert-butyl4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate (100 mg,0.31 mmol) in DCM (15 mL) at −78° C. was treated dropwise with DAST(0.08 mL, 0.6 mmol). The resulting mixture was stirred at −78° C. for 90min. It was then quenched with ice water, warmed to rt, and extractedwith DCM (50 mL). The organic layer was separated, washed with brine,dried over anhydrous Na₂SO₄, filtered, and evaporated under reducedpressure to obtain 70 mg of (±)-rel-(3S,4S)-tert-butyl3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate. LCMS(Method P) RT 1.11, 1.13 min, m/z 313 (M+H⁺+CH₃CN-t-butyl). Threebatches of product (˜210 mg total) were combined and subjected to HPLCpurification (Method A) to give 140 mg (±)-rel-(3S,4S)-tert-butyl3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.43 (s, 9H) 1.55-1.67 (m, 1H) 1.74-1.82 (m,1H) 2.72-2.90 (m, 3H) 3.82 (s, 3H) 3.89-4.03 (m, 1H) 4.24-4.34 (m, 1H)4.50-4.71 (m, 1H) 7.09 (d, J=1.51 Hz, 2H) 7.18-7.28 (m, 1H).

Step F. (3R,4R)-tert-Butyl3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate and(3S,4S)-tert-butyl3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate

The purified product from step F was subjected to chiral SFC (method D)to afford the two separate enantiomers (E-1 and E-2). Data for E-1(3S,4S)-tert-butyl3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate: chiralHPLC (method G) RT=2.45 min, 100% AP; LCMS (Method J) RT=1.04 min,m/z=252 (M+H+-HF, -t-butyl), 272 (M+H⁺-t-butyl); ¹H NMR (400 MHz,methanol-d₄) δ ppm 7.02-7.11 (m, 3H) 4.36-4.59 (m, 2H) 4.07-4.16 (m, 1H)3.87 (s, 3H) 2.76-2.95 (m, 3H) 1.82-1.93 (m, 1H) 1.64-1.76 (m, 1H) 1.51(s, 9H). Data for E-2 (3R,4R)-tert-butyl3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate: chiralHPLC (method G) RT=2.82 min, 96.9% AP; LCMS (Method J) RT=1.04 min,m/z=252 (M+H+-HF, -t-butyl), 272 (M+H⁺-t-butyl); ¹H NMR (400 MHz,methanol-d₄) δ ppm 7.05 (m, 3H) 4.39-4.60 (m, 2H) 4.07-4.16 (m, 1H) 3.87(s, 3H) 2.76-2.94 (m, 3H) 1.84-1.91 (m, 1H) 1.63-1.76 (m, 1H) 1.51 (s,9H).

Step G. (3S,4S)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine,hydrochloride

To a stirring solution of (3S,4S)-tert-butyl3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate (E-1, thefirst eluting enantiomer from step F, 44 mg, 0.134 mmol) in 1,4-dioxane(3 mL) at 0° C. was added 2 mL (8 mmol) of 4 M HCl in dioxane, and theresulting mixture was stirred at rt for 12 h. The solvent was removedunder reduced pressure to afford(3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine hydrochloride(30 mg) as a white solid which was used without further purification.LCMS (Method J) RT=0.60 min, m/z 228.2 (M+H⁺). ¹H NMR (400 MHz,methanol-d₄) δ ppm 7.01-7.19 (m, 3H) 4.88-4.99 (m, 1H) 4.71-4.83 (m, 1H)3.89 (s, 3H) 3.67-3.78 (m, 1H) 3.40-3.53 (m, 1H) 3.00-3.25 (m, 3H)2.12-2.27 (m, 1H) 1.93-2.08 (m, 1H).

Step H.3-((3S,4S)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

A mixture of (3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidinehydrochloride (30 mg, 0.11 mmol, from step G),3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (54 mg, 0.19 mmol,intermediate 6) and DIPEA (0.02 mL, 0.11 mmol) in DMF (3 mL) was heatedto 120° C. for 90 min in a microwave reactor. The reaction mixture wascooled to rt and the solvent was removed under reduced pressure toobtain 60 mg of3-((3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)-pyrrolidin-2-one(diastereomeric pair), which was used in the next step withoutpurification. LCMS (Method P) RT=1.12 min, m/z 433 (M+H⁺).

Step I.3-((3S,4S)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

To a stirring solution of3-((3S,4S)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one(60 mg, 0.14 mmol, diastereomeric mixture from step H) in 10 mL of DCMat −78° C. was added 2.5 mL of boron tribromide (2.5 mmole) and themixture allowed to warm to rt and stirred for 3 h. The reaction mixturewas then cooled to 0° C. and quenched with saturated NaHCO₃ solution.The mixture was then diluted with DCM and the organic layer wasseparated and evaporated under reduced pressure. The crude compound waspurified by preparative HPLC to give3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methyl-benzyl)pyrrolidin-2-one(20 mg, 0.047 mmol, 34% yield) (diastereomeric pair). LCMS (Method Q)RT=1.17 min, m/z 419.0 (M+H⁺).

Step J.(S)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-oneand(R)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

The product mixture from step I was subjected to chiral separation viaSFC method C-6 to give two homochiral products: Example 45, P-1 (4.1 mg)and Example 45, P-2 (7.3 mg). Data for P-1(S)-3-(3S,4S)-(3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one:HPLC (Method C) RT=7.09 min (Method D) RT=7.88 min; LCMS (Method F)RT=2.1 min, m/z 419 (M+H⁺). Chiral HPLC (Method C-6) RT=2.87 min; ¹H NMR(400 MHz, methanol-d₄) δ ppm 1.76-1.94 (m, 2H) 1.99-2.12 (m, 1H)2.14-2.24 (m, 1H) 2.25-2.29 (m, 3H) 2.39-2.50 (m, 1H) 2.52-2.71 (m, 2H)2.94-3.06 (m, 1H) 3.07-3.19 (m, 1H) 3.22-3.31 (m, 2H) 3.69-3.80 (m, 1H)4.38-4.68 (m, 3H) 6.81-7.04 (m, 5H) 7.19-7.29 (m, 1H). Data for P-2(R)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one:HPLC (Method C) RT=7.10 min (Method D) RT=7.88 min; LCMS (Method F)RT=2.098 min, m/z 419 (M+H⁺). Chiral HPLC (Method C-6) RT=5.33 min; ¹HNMR (400 MHz, methanol-d₄) δ ppm 1.72-1.90 (m, 2H) 2.02-2.14 (m, 1H)2.15-2.23 (m, 1H) 2.23-2.29 (m, 3H) 2.38-2.49 (m, 1H) 2.53-2.72 (m, 2H)2.73-2.82 (m, 1H) 3.22-3.32 (m, 2H) 3.38-3.47 (m, 1H) 3.59-3.64 (m, 1H)3.69-3.76 (m, 1H) 4.38-4.54 (m, 2H) 4.60-4.71 (m, 1H) 6.85-7.04 (m, 5H)7.20-7.28 (m, 1H).

Step K. (3R,4R)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidinehydrochloride

To a stirring solution of (3R,4R)-tert-butyl3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate (38 mg,0.12 mmol, E-2, the second eluting enantiomer from step F) in 3 mL of1,4-dioxane at 0° C. was added 2 mL of 4M HCl in 1,4-dioxane (8 mmol)and the mixture was allowed to warm up to rt over 12 h. The solvent wasremoved under reduced pressure to obtain(3R,4R)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine hydrochloride(30 mg) as a semi-solid which was used without further purification.LCMS (Method K) RT=0.59 min, m/z 228, m/z 419 (M+H⁺); ¹H NMR (400 MHz,methanol-d₄) δ ppm 6.99-7.22 (m, 3H) 4.73-4.84 (m, 1H) 3.89 (s, 3H)3.67-3.78 (m, 2H) 3.41-3.52 (m, 1H) 3.00-3.25 (m, 3H) 2.09-2.26 (m, 1H)1.88-2.08 (m, 1H).

Step L.3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

A mixture of (3R,4R)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidinehydrochloride (30 mg, 0.114 mmol, from step K),3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (54 mg, 0.189 mmol,intermediate 6) and DIPEA (0.020 mL, 0.114 mmol) in DMF (3 mL) washeated to 120° C. for 90 min in the a microwave reactor. The solvent wasthen removed under reduced pressure to obtain 60 mg of3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one(diastereomeric pair) which was used in the next step without furtherpurification. LCMS (Method P) RT=1.12 min, m/z 433 (M+H⁺).

Step M.3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

To a stirred solution of3-((3R,4R)-3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one(diastereomeric pair from step L, 50 mg, 0.12 mmol) in DCM (5 mL) at−78° C. was added boron tribromide (2 mL, 2 mmol, 1 M in DCM) and theresulting mixture was stirred at rt for 3 h. The solvent was evaporatedand the residue subjected to preparative HPLC (method D) to yield 20 mg(0.04 mmol, 37%) of3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one(diastereomeric pair). LCMS (Method K) RT 1.16 min; m/z 419 (M+H⁺); ¹HNMR (400 MHz, methanol-d₄) δ ppm 7.22-7.29 (m, 1H) 6.90-7.09 (m, 5H)4.88-4.96 (m, 1H) 4.49-4.53 (m, 2H), 4.12-4.25 (m, 1H), 4.35-4.42 (m,1H) 3.98-4.02 (m, 1H) 3.34-3.48 (m, 4H) 3.14-3.21 (m, 1H) 2.98-3.07 (m,1H) 2.46-2.56 (m, 1H) 2.20-2.30 (m, 5H) 1.98-2.12 (m, 1H).

Step N.(S)-3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-oneand(R)-3-((3R,4R)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

The product mixture from step M was subjected to chiral separation viaSFC (method C-6) to give two homochiral products: Example 45, P-3 (3.6mg) and Example 45, P-4 (2.2 mg). Data for P-3(S)-3-(3R,4R)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one:HPLC (Method C) RT=7.03 min (Method D) RT=8.3 min, LCMS (Method F)RT=2.10 min, m/z 419.2 (M+H⁺), Chiral HPLC (Method C-6) RT=3.6 min; ¹HNMR (400 MHz, methanol-d₄) δ ppm 1.73-1.90 (m, 2H) 2.02-2.24 (m, 2H)2.25-2.31 (m, 3H) 2.39-2.48 (m, 1H) 2.52-2.71 (m, 2H) 2.74-2.82 (m, 1H)3.13-3.30 (m, 2H) 3.38-3.47 (m, 1H) 3.67-3.76 (m, 1H) 4.37-4.70 (m, 4H)6.82-7.04 (m, 5H) 7.18-7.28 (m, 1H). Data for P-4(R)-3-((3R,4R)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one:HPLC (Method C) RT=7.05 min (Method D) RT=8.33 min, LCMS (Method F)RT=2.10 min, m/z 419.2 (M+H⁺), Chiral HPLC (Method C-6) RT=5.44 min; ¹HNMR (400 MHz, methanol-d₄) δ ppm 1.67-1.93 (m, 2H) 2.01-2.13 (m, 1H)2.14-2.23 (m, 1H) 2.25-2.28 (m, 3H) 2.39-2.51 (m, 1H) 2.52-2.72 (m, 2H)2.97-3.07 (m, 1H) 3.09-3.18 (m, 1H) 3.22-3.32 (m, 2H) 3.68-3.78 (m, 1H)4.38-4.55 (m, 2H) 4.58-4.70 (m, 1H) 6.84-7.05 (m, 5H) 7.19-7.28 (m, 1H).

Example 46 (Peak-1, Peak-2, Peak-3, Peak-4)(S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-oneand(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-oneand(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

Step A. (±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol

To a suspension of sodium tetrahydroborate (2.7 g, 72 mmol) in THF (200mL) at 0° C. under a nitrogen atmosphere was added dropwise borontrifluoride etherate (8.8 mL, 70 mmol) and the resulting mixture wasstirred for 30 minutes. Then1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (10 g, 36 mmol,from S. Halazy et al WO 97/28140 (8/7/97)) dissolved in 100 mL oftetrahydrofuran was added. The mixture was allowed to warm to rt andstirred for 2 h. The reaction was then quenched by the dropwise additionof 100 mL of water. Next were added sequentially 100 mL of ethanol, 100mL of a 10% aqueous sodium hydroxide solution, and 30% hydrogen peroxide(18 mL, 180 mmol) and the mixture was stirred at reflux temperatureovernight. The reaction mixture was then allowed to cool, diluted withsaturated aqueous ammonium chloride (200 mL), and extracted with ethylacetate (500 mL). The organic layer was dried over Na₂SO₄, filtered, andevaporated under reduced pressure to give(±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (8.5 g, 24.6mmol, 69% yield) which was used without further purification. LCMS(Method K) RT 1.99 min; m/z 298.0 (M+H⁺).

Step B. (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol

To a solution of(±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (9 g, 30mmol) in methanol (150 mL) was added 10% Pd/C (4.8 g) and the reactionmixture was stirred overnight under a hydrogen atmosphere. The catalystwas then removed by filtration through Celite and the solvent wasevaporated under reduced pressure to give(±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (5.1 g, 24.6 mmol, 81%yield) which was used without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.10-7.15 (m, 2H) 6.80-6.86 (m, 2H) 4.30 (d, J=5.27 Hz,1H) 3.37-3.43 (m, 1H) 3.04 (dd, J=11.58, 4.36 Hz, 1H) 2.86 (d, J=12.17Hz, 1H) 2.43 (td, J=12.09, 2.67 Hz, 1H) 2.22-2.35 (m, 2H) 1.57-1.63 (m,1H) 1.43-1.54 (m, 1H).

Step C. (±)-rel-(3S,4S)-tert-butyl4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate

To a solution of (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (4.5g, 21.7 mmol) in DCM (150 mL) at −10° C. under nitrogen was added a 1 Msolution of boron tribromide in DCM (109 mL, 109 mmol). The reactionmixture was allowed to warm to rt, stirred for 2 h, and then rechilledto 0° C. and quenched by the addition of a saturated aqueous sodiumbicarbonate solution (300 mL). The aqueous layer was washed with 250 mLof DCM and then to it was added 200 mL 10% aqueous NaOH, followed by 9.5g (43.5 mmol) of di-t-butyl dicarbonate and the resulting mixture wasstirred for an additional 2 h. The mixture was then extracted with 200mL ethyl acetate and the organic layer was separated, dried over Na₂SO₄,filtered, and evaporated under reduced pressure to(±)-rel-(3S,4S)-tert-butyl4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate(6.5 g, 12 mmol, 56% yield) which was used without further purification.LCMS (Method K) RT 2.33 min, m/z 282 (M+H⁺-2 t-butyl), 370; ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.27 (d, J=8.66 Hz, 2H) 7.08 (d, J=8.66 Hz, 2H) 4.85(d, J=5.65 Hz, 1H) 4.13 (d, J=8.41 Hz, 1H) 3.97 (d, J=10.48 Hz, 1H) 3.45(tt, J=10.27, 5.19 Hz, 1H) 1.67 (d, J=3.39 Hz, 1H) 1.50-1.59 (m, 1H)1.49 (s, 11H).

Step D. (±)-rel-(3S,4S)-tert-butyl3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate

To a solution of (±)-rel-(3S,4S)-tert-butyl4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate(6.5 g, 16.5 mmol) in 100 mL of methanol was added 11.42 g of potassiumcarbonate (83 mmol) and the reaction mixture was stirred at rt for 5 h.The organic solvent was removed under reduced pressure and the residuewas partitioned between 1N HCl (300 mL) and ethyl acetate (300 mL). Thelayers were separated and the organic layer was dried over Na₂SO₄ andevaporated under reduced pressure to give (±)-rel-(3S,4S)-tert-butyl3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (5 g, 15 mmol, 92%yield) which was used without further purification. LCMS (method F) RT1.85 min, m/z 238 (M+H⁺-t-butyl), 279 (M+H⁺-t-butyl+CH₃CN), ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.01 (d, J=8.53 Hz, 2H) 6.66 (d, J=8.53 Hz, 2H) 4.70(d, J=5.02 Hz, 1H) 4.09 (br. s., 1H) 3.94 (d, J=11.55 Hz, 1H) 3.35-3.41(m, 1H) 2.66-2.77 (m, 1H) 2.29-2.39 (m, 1H) 1.63 (dd, J=13.30, 3.26 Hz,1H) 1.44-1.52 (m, 1H) 1.42 (s, 9H).

Step E. (3S,4S)-tert-Butyl3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and(3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate

(±)-rel-(3S,4S)-tert-Butyl3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (5 g, 17 mmol,from step D) was subjected to chiral SFC separation (method C-5) toyield enantiomers E-1 (1.9 g, 6.48 mmol, 38.0% yield) and E-2 (2.4 g,8.18 mmol, 48.0% yield). Data for E-1: chiral HPLC (method A5) retentiontime 3.42 min. Data for E-2: chiral HPLC (method A5) retention time 4.2min.

Step F. (3R,4R)-tert-Butyl4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate

A mixture of (3R,4R)-tert-butyl3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (620 mg, 2.1 mmol,E-2 from step E), potassium carbonate (584 mg, 4.2 mmol), and benzylbromide (0.25 mL, 2.1 mmol) in DMF (5 mL) was stirred at rt for 16 h.The solvent was removed by evaporation and the residue was treated with50 mL of water. The aqueous mixture was then extracted 4 times with 50mL of chloroform. The combined organic phases were dried over anhydrousNa₂SO₄, filtered, and evaporated to yield 750 mg of (3R,4R)-tert-butyl4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate which was usedwithout further purification. LCMS (method F) RT 2.28 min, m/z=310(M+H⁺-t-butyl-water), 328 (M+H⁺-t-butyl).

Step G. (3R,4R)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol hydrochloride

A mixture of (3R,4R)-tert-butyl4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (750 mg, 2mmol), dioxane (4 mL) and 4.9 mL of 4 M HCl in dioxane was stirred at rtfor 2 h. The reaction was then evaporated to dryness to yield 550 mg of(3R,4R)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol hydrochloride which wasused without further purification. LCMS (method J) RT 0.70 min, m/z 284(M+H⁺).

Step H.3-((3R,4R)-4-(4-(Benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (Intermediate 2,220 mg, 0.82 mmol), (3R,4R)-4-(4-(benzyloxy)phenyl)piperidin-3-olhydrochloride (262 mg, 0.82 mmol, from step G) and triethylamine (11 mL,8.2 mmol) was stirred at 60° C. for 1 h, 80° C. for 1 h, 100° C. for 1 hand 120° C. for 1 h. The reaction mixture was then allowed to cool,diluted with 40 mL of water and extracted four times with 50 mL ofchloroform. The combined organic layers were washed with 60 mL brine,dried over anhydrous sodium sulfate, filtered, and evaporated to yield382 mg of3-((3R,4R)-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-onewhich was used without further purification. LCMS (method J) (maincomponent of a mixture) RT 2.23 min, m/z 471 (M+H⁺).

Step I.3-((3R,4R)-4-(4-(Benzyloxy)phenyl)-3-fluoropiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

A solution of3-(-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one(382 mg, 0.81 mmol) in DCM (5 mL) cooled to 0° C. was treated dropwisewith DAST (0.32 mL, 2.4 mmol) over 3 min. The reaction mixture was thenallowed to warm to rt and was stirred for 2 h. The reaction was thenquenched with 50 mL of 10% aqueous sodium bicarbonate solution andextracted 4 times with 40 mL of DCM. The combined organic layers werewashed with 50 mL of brine, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum to yield 382 mg of3-((3R,4R)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-oneas a mixture of two diastereomers and rearrangement products which wasused without further purification. LCMS (method J) (main component of amixture) RT 0.9 min, m/z 473 (M+H⁺).

Step J.3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

A mixture of3-((3R,4R)-(4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one(382 mg, 0.81 mmol) and methanol (4 mL) was flushed with nitrogen,followed by the addition of 172 mg of 10% Pd/C. Then the mixture wasstirred at rt overnight under 25-99 psi hydrogen pressure. The reactionwas then transferred to a 100 mL autoclave and stirred at 7 kg/cm²hydrogen pressure for 4 days. The catalyst was removed by filtrationthrough Celite and the solvent was evaporated off. The crude product wassubjected to HPLC purification (method B) to yield 77.3 mg3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one(diastereomeric pair) LCMS (method Q) RT 1.15 min, m/z 383.0 (M+H⁺).

Step K.(S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-oneand(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

The diastereomeric mixture from step J was separated by SFC method C-7to yield homochiral Examples 46 P-1 (29.3 mg) and P-2 (32.8 mg). Datafor P-1(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one:LCMS (method F) RT 2.10 min, m/z 383.2 (M+H⁺), 405.2 (M+Na⁺); HPLC(method B) RT 8.24 min (98.8% AP); HPLC (method C) RT 6.52 min (99.1%AP); Chiral HPLC (method C-6) RT 4.1 min; ¹H NMR (400 MHz, methanol-d₄)δ ppm 1.76-1.86 (m, 2H) 2.07 (d, J=8.53 Hz, 1H) 2.13-2.21 (m, 1H) 2.34(s, 3H) 2.43 (s, 0H) 2.55-2.60 (m, 1H) 2.65-2.70 (m, 1H) 2.75 (br. s.,1H) 3.20-3.30 (m, 2H) 3.38-3.45 (m, 1H) 3.70 (t, J=8.78 Hz, 1H) 4.44 (t,J=79.81 Hz, 3H) 4.63-4.71 (m, 1H) 6.70-6.80 (m, 2H) 7.07-7.15 (m, 2H)7.07-7.12 (m, 1H) 7.13-7.22 (m, 4H); ¹⁹F NMR δ ppm −184.171. Data forP-2:(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one:LCMS (method F) RT 2.10 min, m/z 383.2 (M+H⁺), 405.2 (M+Na⁺); HPLC(method B) RT 8.29 min (99.7% AP); HPLC (method C) RT 6.52 min (99.8%AP); Chiral HPLC (method C-6) RT 6.92 min; ¹H NMR (400 MHz, methanol-d₄)δ ppm 1.80-1.90 (m, 2H) 2.07 (d, J=8.03 Hz, 1H) 2.19 (s, 1H) 2.34 (s,3H) 2.41-2.48 (m, 1H) 2.66 (d, J=4.52 Hz, 2H) 2.95-3.03 (m, 1H)3.10-3.18 (m, 1H) 3.20-3.30 (m, 2H) 3.68-3.78 (m, 1H) 4.38 (s, 1H) 4.51(d, J=14.56 Hz, 2H) 6.70-6.80 (m, 2H) 7.05-7.13 (m, 2H) 7.13-7.22 (m,4H); ¹⁹F NMR δ ppm −184.311.

Step L. (3S,4S)-tert-Butyl3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate

To a solution of (3S,4S)-tert-butyl3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (400 mg, 1.36mmol, the first eluting enantiomer E-1 from step E) in DCM (5 mL) cooledto 0° C. was added dropwise DAST (0.54 mL, 4.1 mmol) over 10 min. Themixture was allowed to warm up to rt and was stirred for 2 h. Thereaction was slowly quenched with 50 mL of a 10% aqueous sodiumbicarbonate solution and extracted four times with 50 mL of DCM. Thecombined organic layers were washed with 75 mL of brine, dried, andconcentrated under vacuum to yield 390 mg of (3S,4S)-tert-butyl3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate which was usedwithout further purification. LCMS (Method Q) RT 0.92 min, m/z 240.1(M+H⁺).

Step M. 4-((3S,4S)-3-Fluoropiperidin-4-yl)phenol hydrochloride

A mixture of (3S,4S)-tert-butyl3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (390 mg, 1.3 mmol)and 4M HCl in dioxane (3.3 mL, 13.2 mmol) in dioxane (4 mL) was stirredat rt for 2 hr. It was then concentrated to dryness, washed with 10 mLof 5% DCM/diethyl ether mixture and the solid was isolated byfiltration. Yield: 260 mg of 4-((3S,4S)-3-fluoropiperidin-4-yl)phenolhydrochloride; LCMS (method Q) RT 0.46 min, mz 196.1 (M+H⁺)¹H NMR (400MHz, DMSO-d₆) δ=9.57 (br. s., 4H), 8.92-8.68 (m, 1H), 7.14 (d, J=8.5 Hz,1H), 7.06 (d, J=8.5 Hz, 2H), 6.82-6.73 (m, 2H), 5.07-4.85 (m, 1H),3.77-3.36 (m, 9H), 3.32-3.22 (m, 2H), 3.13-2.85 (m, 5H), 2.06-1.88 (m,H).

Step N.3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (200 mg, 0.75mmol), triethylamine (0.52 mL, 3.7 mmol) and4-((3S,4S)-3-fluoropiperidin-4-yl)phenol hydrochloride (173 mg, 0.75mmol) in DMF (3 mL) was heated to 120° C. in a microwave reactor for 1.5h. The mixture was allowed to cool and was then mixed with 60 mL waterand extracted 5 times with 40 mL of DCM. The combined organic extractswere washed with 80 mL of brine, dried over anhydrous sodium sulfate,filtered, and evaporated to give 265 mg of3-((3S,4S)-3-fluoro-4-(4-hydroxy-phenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-oneas a mixture of 2 diastereoisomers. LCMS (method P) RT 0.92 min m/z383.4 (M+H⁺).

Step O.(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-oneand(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

A portion of the diastereomer mixture from step N (130 mg) was subjectedto chiral purification via SFC (method C-7) to give homochiral Examples46 P-3 (37.7 mg) and P-4 (60.7 mg). Data for P-3(S)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one:LCMS (Method F) RT=2.10 min, m/z 383.2 (M+H⁺); HPLC (Method C) RT 6.54min, (Method D) RT 8.20 min; chiral HPLC (method C-6) RT 3.42 min; ¹HNMR (400 MHz, methanol-d₄) δ ppm 1.76-1.86 (m, 2H) 2.06 (d, J=8.53 Hz,1H) 2.10-2.21 (m, 1H) 2.34 (s, 3H) 2.40-2.48 (m, 1H) 2.53-2.60 (m, 1H)2.61-2.70 (m, 2H) 2.95-3.01 (m, 1H) 3.01 (s, 2H) 3.10-3.16 (m, 1H)3.18-3.28 (m, 2H) 3.72 (s, 1H) 4.35-4.41 (m, 1H) 4.46-4.70 (m, 2H)6.72-6.80 (m, 2H) 7.05-7.23 (m, 6H). Data for P-4(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one:LCMS (Method F) RT 2.11 min, m/z 383.2 (M+H⁺); HPLC (Method C) RT 6.50min, (Method D) RT 8.21 min; chiral HPLC (method C-6) RT 6.31 min; ¹HNMR (400 MHz, methanol-d₄) δ ppm 1.81 (dd, J=7.28, 2.76 Hz, 2H) 2.06 (d,J=9.04 Hz, 2H) 2.33 (s, 3H) 2.43 (s, 1H) 2.55 (br s, 1H) 2.66 (d,J=40.16 Hz, 2H) 2.75-2.80 (m, 1H) 2.96-3.10 (m, 2H) 3.20-3.28 (m, 2H)3.41 (d, J=5.52 Hz, 1H) 3.66-3.75 (m, 1H) 4.31-4.41 (m, 1H) 4.46-4.71(m, 2H) 6.76 (d, J=8.53 Hz, 2H) 7.05-7.23 (m, 6H).

Example 47(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one,(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one,(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one,and(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

Step A.(±)-rel-1-(3-Fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one

To a solution of 3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one(Intermediate 6, 200 mg, 0.7 mmol) and(±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (145 mg, 0.7 mmol,from Example 46, step B) in acetonitrile (15 mL) was added triethylamine(0.1 mL, 0.7 mmol) and the resulting mixture was heated in the microwaveat 100° C. for 1 h. The cooled reaction mixture was diluted with asaturated ammonium chloride solution and extracted with ethyl acetate(100 mL). The organic layer was separated, dried over Na2SO4, filtered,and evaporated under reduced pressure to give(±)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one(280 mg, 0.51 mmol, 73% yield, mixture of 4 diastereoisomers), which wasused directly in the next step. LCMS (Method F) RT 1.99 min m/z 413.2(M+H⁺).

Step B.(±)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

To a solution of(±)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one(300 mg, 0.73 mmol) in DCM (20 mL) under nitrogen at −10° C. was addedboron tribromide (0.17 mL, 1.8 mmol) and the reaction mixture wasstirred at rt for 1 h. The reaction was then quenched with saturatedsodium bicarbonate solution and extracted with 200 mL of ethyl acetate.The organic layer was separated, dried over Na₂SO₄, filtered, andevaporated under reduced pressure to give(±)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(290 mg, 0.36 mmol, 50% yield, mixture of 4 diastereoisomers); LCMS(Method F) RT 1.854 min m/z 399.2 (M+H⁺).

Step C.(±)-rel-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

To a solution of(±)-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(280 mg, 0.7 mmol) in DCM (20 mL) was added DAST (0.5 mL, 3.5 mmol) andthe reaction mixture was stirred under nitrogen for 1 h. The reactionwas then quenched by the addition of 100 mL of a saturated sodiumbicarbonate solution and the mixture was diluted with 100 mL of ethylacetate. The organic layer was separated, dried over Na₂SO₄, filtered,and evaporated under reduced pressure. The residue was subjected topreparative HPLC (method B) to yield 22 mg of(±)-rel-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-oneas a mixture of 4 diastereomers. LCMS (method P) RT 1.64 min; m/z=401.0(M+H⁺).

Step D.(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one,(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one,(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one,and(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

The compound(±)-rel-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one(85 mg, 0.212 mmol) isolated from Step C was separated into thehomochiral Examples 47 P-1, P-2, P-3, and P-4 via chiral SFC (method I):Data for P-1(S)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)-pyrrolidin-2-one:LCMS (Method F) RT 2.03 min, m/z 401 (M+H⁺); HPLC (Method A) RT=6.73 min(96.8% AP), (method B) RT=7.719 min (97% AP); Chiral SFC (Method E) RT5.17 min (100% AP); ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.84 (dd,J=7.28, 3.26 Hz, 2H) 2.01-2.27 (m, 5H) 2.39-2.68 (m, 3H) 2.97-3.06 (m,1H) 3.15 (s, 1H) 3.22-3.30 (m, 1H) 3.73 (t, J=8.78 Hz, 1H) 4.38-4.71 (m,3H) 6.73-6.79 (m, 2H) 6.93-7.03 (m, 2H) 7.08-7.16 (m, 1H) 7.23 (t,J=7.53 Hz, 1H). Data for P-2(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)-pyrrolidin-2-one:LCMS (Method F) RT 2.30 min, m/z 401 (M+H⁺); HPLC (Method A) RT=6.71 min(99% AP), Method B RT=7.73 min (98.1% AP); Chiral SFC (Method E) RT 6.21min (96.5% AP); ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.74-1.86 (m, 2H)2.03-2.13 (m, 1H) 2.15-2.27 (m, 4H) 2.43 (td, J=10.04, 4.52 Hz, 1H)2.50-2.71 (m, 2H) 2.76 (d, J=1.51 Hz, 1H) 3.20-3.30 (m, 2H) 3.38-3.46(m, 1H) 3.71 (t, J=9.04 Hz, 1H) 4.37-4.70 (m, 3H) 6.72-6.78 (m, 2H)6.92-7.02 (m, 2H) 7.09-7.13 (m, 1H) 7.23 (t, J=7.78 Hz, 1H). Data forP-3(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)-pyrrolidin-2-one:LCMS (Method F) RT 2.04 min, m/z 401 (M+H⁺); HPLC (Method A) RT=6.68 min(98% AP), (Method B) RT=7.70 min (99.2% AP); Chiral SFC (Method E) RT7.22 min (98.5% AP); ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.74-1.86 (m,2H) 2.02-2.27 (m, 5H) 2.43 (td, J=10.04, 5.02 Hz, 1H) 2.50-2.72 (m, 3H)2.73-2.82 (m, 3H) 3.23-3.30 (m, 2H) 3.38-3.46 (m, 1H) 3.71 (t, J=8.78Hz, 1H) 4.36-4.72 (m, 4H) 6.73-6.79 (m, 2H) 6.94-7.02 (m, 2H) 7.08-7.14(m, 2H) 7.23 (t, J=7.78 Hz, 1H). Data for P-4(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one:LCMS (Method F) RT: 2.03 min, m/z 401 (M+H⁺). HPLC (Method A) RT=6.71min (90% AP); (Method B) RT=7.68 min (91.5% AP); Chiral SFC (Method E)RT 7.89 min (97% AP); ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.78-1.88 (m,2H) 2.09 (d, J=8.53 Hz, 1H) 2.26 (d, J=2.01 Hz, 4H) 2.40-2.47 (m, 1H)2.66 (d, J=4.52 Hz, 2H) 2.96-3.06 (m, 1H) 3.15 (s, 1H) 3.21-3.30 (m, 2H)3.73 (s, 1H) 4.37-4.69 (m, 3H) 6.72-6.79 (m, 2H) 6.94-7.03 (m, 2H)7.07-7.13 (m, 1H) 7.23 (t, J=7.53 Hz, 1H).

Step E. (3R,4R)-4-(4-Hydroxyphenyl)piperidin-3-ol hydrochloride

To a solution of (3R,4R)-tert-butyl3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (1.5 g, 5.1 mmol,E-2 from example 46 step E) in methanol (50 mL) under nitrogen was added12.8 mL of 4 M HCl in dioxane and the reaction was stirred for 1 h atrt. The mixture was then evaporated under reduced pressure to drynessand the residue was washed twice with 20 mL of diethyl ether. The solidresidue was dried under vacuum to give(3R,4R)-4-(4-hydroxyphenyl)-piperidin-3-ol hydrochloride E-2a (950 mg,4.1 mmol). LCMS (method F) RT: 0.17 min, m/z 194 (M+H⁺). ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.74-1.93 (m, 2H) 2.61-2.68 (m, 1H) 2.81-2.93 (m,1H) 3.21-3.33 (m, 2H) 3.78-3.90 (m, 1H) 6.72 (d, J=8.53 Hz, 2H) 7.00 (d,J=8.53 Hz, 2H) 9.14-9.25 (m, 1H) 9.27-9.44 (m, 1H).

Step F.1-(3-Fluoro-4-methylbenzyl)-3-((3R,4R)-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

To a solution of racemic3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one (1.5 g, 5.2 mmol,Intermediate 6) and (3R,4R)-4-(4-hydroxyphenyl)piperidin-3-ol, HCl (1.2g, 5.2 mmol) in acetonitrile (20 mL) was added triethylamine (2.2 mL,15.7 mmol) and the resulting mixture was heated for 5 h at 60° C. Thereaction mixture was then evaporated and the residue was diluted withsaturated ammonium chloride solution and extracted with 200 mL of ethylacetate. The layers were separated and the organic layer was washed withbrine, dried over Na₂SO₄, filtered, and evaporated to yield1-(3-fluoro-4-methylbenzyl)-3-((3R,4R)-3-hydroxy-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one(1.9 g, 4 mmol) as a mixture of two diastereomers. LCMS (method F) RT1.93 min, m/z 399 (M+H⁺).

Step G.3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

To a solution of1-(3-fluoro-4-methylbenzyl)-3-((3R,4R)-3-hydroxy-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one(from step F, 1.9 g, 4.8 mmol) in DCM (35 mL) at 0° C. was added DAST(3.2 mL, 23.8 mmol) under nitrogen. The reaction mixture was allowed towarm to rt and stirred for 2 h, and then diluted with saturatedbicarbonate solution and extracted with 200 mL of DCM. The organic layerwas dried over Na₂SO₄, filtered, and evaporated under reduced pressureto give a crude product which was purified via preparative HPLC (methodJ) to yield3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one(1.1 g, 2.6 mmol) as a pair of diastereomers. LCMS (Method F) RT: 2.13min, m/z 401. (M+H)⁺.

Step H,(R)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

The mixture of diastereomers of3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one(1.1 g) from step G was separated by chiral SFC chromatography (methodJ). The second-eluting isomer,(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one,was isolated (355 mg) and its data was consistent with those of Example47, P-4. LCMS (Method F) RT 2.14 min, m/z 401 (M+H⁺); HPLC (Method A) RT6.70 min (99.6% AP), (Method B) RT 8.16 min (99.7% AP); Chiral SFC(Method E) RT 7.62 (100% AP); ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.85(dd, J=7.28, 2.76 Hz, 2H) 2.09 (d, J=8.03 Hz, 1H) 2.13-2.27 (m, 4H) 2.45(s, 1H) 2.51-2.60 (m, 1H) 2.61-2.71 (m, 1H) 2.98-3.06 (m, 1H) 3.15 (s,1H) 3.23-3.30 (m, 1H) 3.62 (s, 1H) 3.69-3.77 (m, 1H) 4.39-4.70 (m, 4H)6.72-6.80 (m, 2H) 6.95-7.03 (m, 2H) 7.09-7.15 (m, 2H) 7.24 (t, J=7.78Hz, 1H).

Example 48 (Peak 1, Peak 2, Peak 3, Peak 4)(S)-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one,(S)-1-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one,(R)-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one,and(R)-1-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Step A.(±)-rel-1-(4-Fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one

To a solution of 3-bromo-1-(4-fluorobenzyl)pyrrolidin-2-one(Intermediate 1, 300 mg, 1.1 mmol) andtrans-4-(4-methoxyphenyl)piperidin-3-ol (from Example 46, step B, 240mg, 1.16 mmol) in acetonitrile (10 mL) was added triethylamine (560 mg,5.5 mmol) and the mixture was heated at 120° C. in a microwave reactorfor 1 h. The reaction mixture was then diluted with water and extractedwith 100 mL of ethyl acetate. The organic layer was dried over Na₂SO₄,filtered, and evaporated under reduced pressure to give(±)-rel-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one(450 mg, 0.7 mmol) as a mixture of four diastereomers which was usedwithout further purification. LCMS (Method S) RT 1.89 min, m/z 399.1(M+H⁺).

Step B.(±)-rel-3-((3S,4S)-3-Fluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one

To a solution of1-(4-fluorobenzyl)-3-(trans-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-onefrom step B (2.5 g, 6.3 mmol) in 50 mL DCM was added DAST (4.1 mL, 31mmol) and the reaction was stirred at ambient temperature for 1 h. Thereaction was then quenched with a sat. bicarbonate solution (200 mL) andthe mixture was extracted with 200 mL of DCM. The organic layer wasdried over Na₂SO₄, filtered, and evaporated under reduced pressure. Theresidue was purified via silica gel chromatography eluting with 28%ethyl acetate in hexane to give(±)-rel-3-((3S,4S)-3-fluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one(900 mg, 1.6 mmol) as a mixture of four diastereomers. LCMS (method P)RT 0.89 min, m/z 401.2 (M+H⁺).

Step C.3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one

To a solution of(trans-3-fluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one(700 mg, 1.75 mmol) in 50 mL of DCM at 0° C. was added BBr₃ (0.3 mL, 3.5mmol). The reaction mixture was allowed to warm up to room temperatureover 1 h. The mixture was then diluted with a sat. bicarbonate solutionand extracted with 200 mL of DCM. The organic layer was dried overNa2SO4, filtered, and evaporated under reduced pressure.

The residue was purified by preparative HPLC (method A) to yield 120 mgof3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-oneas a mixture of four diastereomers. LCMS (method N) RT 1.45 min, m/z387.0 (M+H⁺).

Step D.(S)-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one,(S)-1-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one,(R)-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one,and(R)-1-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one

The diastereomeric mixture from step C was separated via chiral SFC(method F) into the 4 homochiral diastereomers, Example 48 P-1, P-2,P-3, and P-4. Data for P-1(S)-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one:Chiral SFC (Method F) RT 3.32 min, 100% AP; HPLC (Method A) RT 6.53 min,96.0% AP, (Method B) RT 6.7 min, 96.3% AP; LCMS (Method F) RT 2.02 min,m/z 387.0 (M+H⁺); ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.32 (dd, J=8.78,5.27 Hz, 2H) 7.07-7.14 (m, 4H) 6.76 (d, J=8.53 Hz, 2H) 4.41-4.56 (m, 2H)3.74 (t, J=8.78 Hz, 1H) 3.23-3.31 (m, 2H) 3.10-3.17 (m, 1H) 3.01 (d,J=11.04 Hz, 1H) 2.88 (d, J=7.03 Hz, 1H) 2.66 (td, J=10.04, 4.52 Hz, 1H)2.57 (dd, J=10.54, 6.53 Hz, 1H) 2.40-2.49 (m, 1H) 2.16-2.25 (m, 1H)2.03-2.13 (m, 1H) 1.80-1.88 (m, 2H). Data for P-2(S)-1-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one:Chiral SFC (Method F) RT 4.15 min, 99.7% AP; HPLC (Method A) RT 6.52min, 98.1% AP, (Method B) RT 6.92 min, 98.6% AP; LCMS (Method F) RT 2.03min, m/z 387.0 (M+H⁺); ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.29-7.34 (m,2H) 7.07-7.14 (m, 4H) 6.76 (d, J=9.04 Hz, 2H) 3.71 (t, J=8.78 Hz, 1H)3.39-3.45 (m, 1H) 3.24-3.31 (m, 2H) 2.74-2.80 (m, 1H) 2.64-2.72 (m, 1H)2.57 (dd, J=10.54, 6.02 Hz, 1H) 2.43 (td, J=10.04, 5.02 Hz, 1H)2.15-2.25 (m, 1H) 2.05-2.14 (m, 1H) 1.77-1.85 (m, 2H). Data for P-3(R)-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one:Chiral SFC (Method F) RT 4.56 min, 97.4% AP; HPLC (Method A) RT 6.53min, 96.0% AP, (Method B) RT 6.94 min, 96.4% AP; LCMS (Method F) RT 2.02min, m/z 387.0 (M+H⁺); ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.29-7.34 (m,2H) 7.07-7.13 (m, 4H) 6.74-6.78 (m, 2H) 4.40-4.55 (m, 2H) 3.71 (t,J=9.04 Hz, 1H) 3.38-3.45 (m, 1H) 3.23-3.31 (m, 2H) 2.76 (br. s., 1H)2.64-2.72 (m, 1H) 2.57 (dd, J=10.54, 6.02 Hz, 1H) 2.43 (td, J=10.04,5.02 Hz, 1H) 2.16-2.25 (m, 1H) 2.05-2.14 (m, 1H) 1.77-1.87 (m, 2H). Datafor P-4(R)-1-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one:Chiral SFC (Method F) RT 5.57 min, 99.9% AP; HPLC (Method A) RT 6.55min, 99.9% AP, (Method B) RT 6.90 min, 99.9% AP; LCMS (Method F) RT 2.03min, m/z 387.0 (M+H⁺); ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.32 (dd,J=8.78, 5.27 Hz, 2H) 7.07-7.14 (m, 4H) 6.76 (d, J=8.53 Hz, 2H) 4.41-4.56(m, 3H) 3.74 (t, J=8.53 Hz, 1H) 3.24-3.32 (m, 2H) 3.10-3.17 (m, 1H) 2.66(td, J=9.91, 4.77 Hz, 1H) 2.57 (dd, J=10.54, 6.53 Hz, 1H) 2.41-2.49 (m,1H) 2.16-2.24 (m, 1H) 2.04-2.12 (m, 1H) 1.80-1.88 (m, 2H).

Example 49 (Peak-1 and Peak-2)(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-oneand(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one

Step A. (3R,4R)-tert-Butyl3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate

To a solution of (3R,4R)-tert-butyl3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (M G Bursavich etal; Organic Letters 2001, 3, 2317, 150 mg, 0.51 mmol) in 5 mL of DCM at−78° C. under nitrogen was added DAST (0.2 mL, 1.5 mmol). The mixturewas allowed to warm up to rt with stirring over 3 h. To the mixture wasadded 100 mL of ethyl acetate and the organic layer was separated,washed with a saturated NaHCO₃ solution, and then evaporated undervacuum. The residue was purified via silica gel chromatography elutingwith 0-100% ethyl acetate/hexanes to give (3R,4R)-tert-butyl3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (120 mg, 0.41mmol); LCMS (Method T) RT 3.09 min, m/z 294.3. (M−H)⁻; ¹H NMR (500 MHz,chloroform-d) δ 7.11 (d, J=8.5 Hz, 2H), 6.93 (br. s., 1H), 6.89-6.82 (m,2H), 4.56-4.47 (m, 1H), 4.45-4.38 (m, 1H), 4.16 (d, J=7.2 Hz, 1H),2.89-2.69 (m, 3H), 1.89-1.83 (m, 1H), 1.76-1.65 (m, 1H), 1.53 (s, 9H).

Step B. 4-((3R,4R)-3-Fluoropiperidin-4-yl)phenol trifluoroacetate

To a solution of (3R,4R)-tert-butyl3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (120 mg, 0.41 mmol)in 1.5 mL DCM at rt was added TFA (0.5 mL, 6.5 mmol), and the mixturewas stirred for 3 h. The mixture was then concentrated in vacuo todryness to yield 4-((3R,4R)-3-fluoropiperidin-4-yl)phenoltrifluoroacetate (126 mg, 0.41 mmol), which was used directly in step D.

Step C. 3-Bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one

To a solution of 2,4-dibromobutanoyl chloride (10 g, 38 mmol) in 100 mLof DCM at 0° C. under nitrogen was added 3-fluoro-4-methylaniline (5.21g, 42 mmol) followed by Et₃N (6.3 mL, 45 mmol). The mixture was stirredat rt for 2 h, then concentrated in vacuo. The residue was dissolved indiethyl ether, then hexanes was added and a solid precipitated. Thesolid was removed by filtration and discarded. The filtrate was thenconcentrated in vacuo to give a dry residue. To a solution of thisresidue in 100 mL DMF at 0° C. under nitrogen was slowly added 60% NaH(1.82 g, 45 mmol). The mixture was stirred and allowed to warm up to rtover 30 min. The reaction mixture was slowly poured into 400 mL of icewater and allowed to stand overnight. A solid formed, and was filteredoff and dried, then purified via silica gel chromatography eluting with0-50% ethyl acetate/hexanes to give racemic3-bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (5.6 g, 20.6 mmol).LCMS (method U) RT 3.41 min, m/z 273.97 (M+H⁺). ¹H NMR (500 MHz,chloroform-d) δ 7.50 (dd, J=11.7, 2.2 Hz, 1H), 7.31-7.27 (m, 1H),7.23-7.17 (m, 1H), 4.60 (dd, J=7.0, 2.9 Hz, 1H), 4.03 (ddd, J=9.8, 7.9,6.8 Hz, 1H), 3.82 (ddd, J=10.0, 7.7, 2.7 Hz, 1H), 2.75 (dq, J=14.6, 7.5Hz, 1H), 2.48 (ddt, J=14.3, 6.7, 2.7 Hz, 1H), 2.28 (d, J=1.7 Hz, 3H).

Step D.(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-oneand(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one

To a solution of 4-((3R,4R)-3-fluoropiperidin-4-yl)phenoltrifluoroacetate, from step B (120 mg, 0.39 mmol) in DMF (2.0 mL) wasadded K₂CO₃ (134 mg, 0.97 mmol) and racemic3-bromo-1-(3-fluoro-4-methyl-phenyl)pyrrolidin-2-one (106 mg, 0.39 mmol,from step C). The mixture was heated to 60° C. and stirred for 30 min.It was then allowed to cool to rt and stirred overnight, followed by theaddition of 50 mL of EtOAc, which induced precipitation of a solid. Thesolid was removed by filtration and discarded, and the filtrate wasconcentrated in vacuo. The residue was purified via silica gelchromatography eluting with a gradient of 0-100% ethyl acetate/hexanesto give 110 mg of (R and S)3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one)as a mixture of two diastereomers. A portion (35 mg) of the diastereomermixture was separated (chiral HPLC method H) into homochiral example 49P-1 (14 mg) and P-2 (14 mg). Data for P-1(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)-pyrrolidin-2-one:Chiral HPLC (method H-2) RT 6.97 min, 98% AP; ¹H NMR (500 MHz,methanol-d₄) δ 7.60-7.52 (m, 1H), 7.32-7.22 (m, 2H), 7.12 (d, J=8.5 Hz,2H), 6.76 (d, J=8.5 Hz, 2H), 4.72-4.65 (m, 1H), 4.63-4.55 (m, 1H), 3.84(d, J=9.2 Hz, 4H), 3.51-3.44 (m, 1H), 2.87-2.80 (m, 1H), 2.76-2.68 (m,1H), 2.64-2.54 (m, 1H), 2.53-2.46 (m, 1H), 2.37-2.30 (m, 1H), 2.26 (d,J=1.4 Hz, 3H), 2.24-2.18 (m, 1H), 1.84 (br s, 3H). Data for P-2(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)-pyrrolidin-2-one:Chiral HPLC (method H-2) RT 8.84 min, 99.3% AP; ¹H NMR (500 MHz,methanol-d₄) δ 7.56 (dd, J=12.0, 1.9 Hz, 1H), 7.32-7.23 (m, 2H), 7.12(d, J=8.4 Hz, 2H), 6.80-6.73 (m, 2H), 4.70-4.63 (m, 1H), 4.60-4.54 (m,1H), 3.88-3.77 (m, 5H), 3.23-3.17 (m, 2H), 3.07 (d, J=10.7 Hz, 2H),2.75-2.68 (m, 2H), 2.64-2.48 (m, 4H), 2.33 (dd, J=6.6, 2.4 Hz, 2H), 2.26(d, J=1.5 Hz, 5H), 2.21 (dd, J=12.7, 9.6 Hz, 2H), 1.90-1.83 (m, 4H).

Example 50 (Peak-1, Peak-2, Peak-3, and Peak 4)(S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)-ethyl)pyrrolidin-2-oneand(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one

(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-oneand(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)-ethyl)pyrrolidin-2-one

Step A. 2,4-Dibromo-N—((S)-1-(4-fluorophenyl)ethyl)butanamide

To a stirred solution of (S)-1-(4-fluorophenyl)ethanamine (3.2 g, 23mmol) in diethyl ether (50 mL) and triethylamine (9.6 mL, 69 mmol) at 0°C. was added 2,4-dibromobutanoyl chloride (7.3 g, 27.6 mmole) and themixture was allowed to warm to rt and stirred for 12 h. A solid formedwhich was removed by filtration, washed with ethyl acetate, and thendiscarded. The combined filtrates were evaporated under reduced pressureand the residue was subjected to silica gel chromatography eluting with20-30% ethyl acetate/petroleum ether yielding 4.5 g of2,4-dibromo-N—((S)-1-(4-fluorophenyl)ethyl)butanamide as a brown solid.LCMS (method O) RT=0.99 min, m/z 366, 368, 370 (M+H⁺, M+H⁺+2, M+H⁺+4);¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25-1.44 (m, 3H) 2.27-2.46 (m, 2H)3.46-3.58 (m, 2H) 4.55-4.66 (m, 1H) 4.81-5.00 (m, 1H) 7.03-7.24 (m, 2H)7.30-7.45 (m, 2H) 8.89 (d, J=8.03 Hz, 1H).

Step B. 3-Bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one

To a stirred solution of2,4-dibromo-N—((S)-1-(4-fluorophenyl)ethyl)butanamide (3 g, 8.2 mmol) intetrahydrofuran (50 mL) at 0° C. was added NaH (1.29 g, 32 mmol) and themixture was allowed to warm to rt and stirred for 3 h. The mixture wasthen poured into ice-cold water and diluted with ethyl acetate. Theorganic phase was separated, washed with brine solution, dried overanhydrous Na₂SO₄, filtered and evaporated under reduced pressureyielding 1.6 g of liquid. The residue was purified by silica gelchromatography eluting with 30% ethyl acetate/petroleum ether to obtain1 g of 3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one as abrown solid (mixture of two diastereomers). LCMS (method O) RT 0.83/0.86min, mz 286/288 (M+H⁺), 308 (M+Na⁺); ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.50 (d, J=7.03 Hz, 3H) 2.08-2.25 (m, 1H) 2.57-2.69 (m, 1H) 2.99 (d,J=10.04 Hz, 1H) 3.35-3.44 (m, 1H) 4.71 (dd, J=7.03, 3.01 Hz, 1H)5.13-5.30 (m, 1H) 7.21 (t, J=9.04 Hz, 2H) 7.30-7.42 (m, 2H).

Step C. tert-Butyl4-(4-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate

To a stirring mixture of tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(16.45 g, 53 mmol), dimethoxyethane (200 mL) and water (50 mL) was added1-(benzyloxy)-4-bromobenzene (14 g, 53 mmol), sodium carbonate (16.9 g,160 mmol) and bis-(triphenylphosphine)palladium(II) chloride (1.867 g,2.66 mmol) at rt. The reaction mixture was purged with nitrogen for 15min, then heated at 80° C. for 4 h. The mixture was allowed to cool tort and then was filtered through Celite and diluted with 200 mL ofwater. The mixture was then extracted three times with 200 mL of ethylacetate and the combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was subjected to silicagel chromatography eluting with 20% ethyl acetate/petroleum ether toobtain 16 g of tert-butyl4-(4-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (16 g, 82%yield) as an off-white solid. LCMS (method O) RT 1.32 min, m/z 366(M+H⁺); ¹H NMR (300 MHz, DMSO-d₆) δ 1.47 (s, 9H), 2.42 (d, J=1.50 Hz,2H), 3.52 (t, J=11.40 Hz, 2H), 3.97 (s, 2H), 5.11 (s, 2H), 6.04 (s, 1H),6.98 (d, J=9.00 Hz, 2H), 7.30-7.46 (m, 7H).

Step D. (±)-rel-(3S,4S)-tert-butyl4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate

To a stirring mixture of NaBH₄ (0.93 g, 24.6 mmol) in THF (25 mL) cooledto 0° C. was added boron trifluoride etherate (3.2 mL, 25 mmol) and themixture was allowed to warm up to rt over 1 h. It was then re-cooled to0° C. and to it was added a solution of tert-butyl4-(4-(benzyloxy)-phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (3 g, 8.2mmol) in THF (10 mL). The resulting mixture was allowed to warm up to rtover 2 h. The reaction mixture was cooled again to 0° C. and H₂O (10mL), ethanol (10 mL), 10 M NaOH (10 mL) and H₂O₂ (8 mL, 26 mmol) weresequentially added. The final mixture was heated to 65° C. overnight.After cooling, the reaction was quenched with water and the mixture wasextracted with ethyl acetate (2×100 mL).

The combined organic layers were dried over Na₂SO₄ and concentrated invacuo yielding 2.7 g of (±)-rel-(3S,4S)-tert-butyl4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (82% yield) asoff-white solid. LCMS (method O) RT 2.41 min, m/z 382 (M−H). ¹H NMR (400MHz, DMSO-d₆) δ 1.41 (s, 9H), 1.63 (m, 1H), 1.67 (m, 1H), 2.67 (m, 1H),3.37-3.41 (m, 1H), 3.92 (m, 1H), 4.10 (m, 1H), 4.73 (d, J=2.4, 1H), 5.07(s, 2H), 6.91 (d, J=9, 2H), 7.14 (d, J=9, 2H), 7.31-7.44 (m, 4H).

Step E. (3S,4S)-tert-Butyl4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate and(3R,4R)-tert-butyl4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate

To a solution of racemic trans-tert-butyl4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (1 g, 2.6mmol, from step D) in DCM (15 mL) cooled to 0° C. was added DAST (1.7mL, 13 mmol) and the mixture was stirred at 0° C. for 15 min. Thereaction was then quenched by the addition of ice water and the mixturewas extracted twice with 20 mL of DCM. The combined organic layers weredried over anhydrous Na2SO4, filtered and concentrated to a pale yellowsolid (1 g). The two desired products were separated from a complexmixture via chiral SFC (method D) to afford E-1 (0.13 g) and E-2 (0.14g). Data for E-1 (3S,4S)-tert-butyl4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate: LCMS (methodP) RT 1.35 min, m/z 330.4 (M-C4H8); chiral HPLC (method G-2) RT 5.8 min;¹H NMR (300 MHz, DMSO-d₆) δ 1.42 (s, 9H), 1.56-1.61 (m, 1H), 1.74-1.78(m, 1H), 2.73-2.84 (m, 3H), 3.94 (d, J=12.30 Hz, 1H), 4.25 (d, J=18.00Hz, 1H), 4.43-4.64 (m, 1H), 5.08 (s, 2H), 6.95 (d, J=8.70 Hz, 2H), 7.23(d, J=8.70 Hz, 2H), 7.32-7.46 (m, 5H). Data for E-2 (3R,4R)-tert-butyl4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate: LCMS (methodP) RT 1.35 min, m/z 330.4 (M-C₄Hs); chiral HPLC (method G-2) RT 6.51min; ¹H NMR (300 MHz, DMSO-d₆) δ 1.42 (s, 9H), 1.56-1.61 (m, 1H),1.74-1.78 (m, 1H), 2.73-2.84 (m, 3H), 3.94 (d, J=12.30 Hz, 1H), 4.25 (d,J=18.00 Hz, 1H), 4.43-4.64 (m, 1H), 5.08 (s, 2H), 6.95 (d, J=8.70 Hz,2H), 7.23 (d, J=8.70 Hz, 2H), 7.32-7.46 (m, 5H).

Step F. (3R,4R)-4-(4-(Benzyloxy)phenyl)-3-fluoropiperidine hydrochloride

To a solution of (3R,4R)-tert-butyl4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (0.12 g, 0.31mmol, E-2 from step E) in 1,4-dioxane (3 mL) was added a 4 M HCl indioxane solution (2 mL, 8 mmol) and the reaction mixture was stirred atrt overnight. The solvent was then evaporated and the solid wastriturated with ethyl acetate and dried to afford E-2a(3R,4R)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine hydrochloride (0.09g, 83% yield) as an off-white solid. LCMS (method O) RT: 0.95 min m/z286 (M+H⁺); ¹H NMR (400 MHz, DMSO-d₆) δ 1.92-1.92 (m, 1H), 2.29-2.33 (m,1H), 3.04-3.14 (m, 3H), 3.45-3.60 (m, 2H), 4.83-4.95 (m, 1H), 5.10 (s,2H), 7.01-7.04 (m, 2H), 7.25-7.31 (m, 2H), 7.32-7.46 (m, 5H), 9.09 (s,1H).

Step G. 4-((3R,4R)-3-Fluoropiperidin-4-yl)phenol hydrochloride

To a solution of (3R,4R)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidinehydrochloride (0.09 g, 0.28 mmol, E-2a from step F) in methanol (3 mL)was added 10% Pd/C (0.09 g) and the mixture was stirred at rt underhydrogen balloon pressure for 12 h.

The mixture was then filtered through Celite and concentrated to affordE-2b 4-((3R,4R)-3-fluoropiperidin-4-yl)phenol hydrochloride (0.06 g, 77%yield) as brown solid. LCMS (method P) RT 0.5 min; m/z 196 (M+H⁺); ¹HNMR (400 MHz, DMSO-d6) δ 1.90-1.94 (m, 2H), 2.90-3.03 (m, 3H), 3.27-3.35(m, 1H), 3.57-3.61 (m, 1H), 4.79-4.97 (m, 1H), 6.75 (d, J=8.40 Hz, 2H),7.05 (d, J=8.80 Hz, 2H), 9.28 (s, 1H), 9.35 (s, 1H).

Step H.(S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)-ethyl)pyrrolidin-2-oneand(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one

A mixture of 3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one(mixture of diastereomers from step B) (60 mg, 0.21 mmol),4-((3R,4R)-3-fluoropiperidin-4-yl)phenol hydrochloride (20.5 mg, 0.1mmol, E-2b from step G) and DIPEA (0.1 mL, 0.6 mmol) in DMF (1 mL) washeated in a microwave reactor at 120° C. for 90 min. The mixture wasallowed to cool and the solvent was then removed under reduced pressure.The diastereomeric products were then separated via preparative HPLC(method B), yielding homochiral examples 50 P-1 (2.4 mg) and P-2 (9.5mg). Data for P-1(S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one:LCMS (method N) RT 1.60 min, m/z 401 (M+H⁺), (method O) RT 1.02 min, m/z401 (M+H⁺); ¹H NMR (400 MHz, methanol-d4) δ ppm 7.30-7.43 (m, 2H)7.05-7.15 (m, 4H) 6.75 (d, J=8.53 Hz, 2H) 5.36-5.46 (m, 1H) 4.46-4.69(m, 1H) 3.64-3.75 (m, 1H) 3.34-3.42 (m, 2H) 3.01-3.10 (m, 1H) 2.48-2.78(m, 3H) 2.33-2.43 (m, 1H) 2.10-2.24 (m, 1H) 1.90-2.04 (m, 1H) 1.71-1.84(m, 2H) 1.55 (d, J=7.53 Hz, 3H). Data for P-2(R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)-pyrrolidin-2-one:LCMS (method N) RT 1.63 min, m/z 401 (M+H⁺), (method O) RT 1.05 min, m/z401 (M+H⁺); ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.30-7.42 (m, 2H)7.06-7.16 (m, 4H) 6.67-6.80 (m, 2H) 5.36-5.50 (m, 1H) 4.60-4.72 (m, 1H)4.50-4.59 (m, 1H) 3.59-3.70 (m, 1H) 3.40-3.54 (m, 2H) 3.08-3.18 (m, 1H)2.87-3.05 (m, 2H) 2.51-2.72 (m, 2H) 2.39-2.49 (m, 1H) 2.00-2.20 (m, 2H)1.75-1.90 (m, 2H) 1.50-1.64 (m, 3H).

Step I. (3S,4S)-4-(4-(Benzyloxy)phenyl)-3-fluoropiperidine hydrochloride

To a solution of (3S,4S)-t-butyl4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (0.12 g, 0.31mmol, E-1 from step E) in 1,4-dioxane (3 mL) was added a 4 M HCl indioxane solution (2 mL, 8 mmol) and the reaction mixture was stirred atrt overnight. The mixture was concentrated in vacuo and the solid wastriturated with ethyl acetate and dried to afford E-1a(3S,4S)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine hydrochloride (0.09g, 88% yield) as an off-white solid. LCMS (method P) RT 0.95 min, m/z286 (M+H⁺); 400 MHz, DMSO-d6: δ 1.94-1.96 (m, 2H), 2.97-3.04 (m, 3H),3.38-3.62 (m, 2H), 4.84-4.95 (m, 1H), 5.10 (s, 2H), 7.00-7.03 (m, 2H),7.17-7.20 (m, 2H), 7.31-7.46 (m, 5H), 9.30 (s, 1H).

Step J. ((3S,4S)-3-Fluoropiperidin-4-yl)phenol

A mixture of (3S,4S)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidinehydrochloride (0.09 g, 0.28 mmol, E-1a from step I) in methanol (3 mL)was added 10% Pd/C (0.09 g) and the reaction mixture was stirred at rtunder hydrogen balloon pressure for 12 h.

The mixture was filtered through Celite and concentrated in vacuo toafford E-1b ((3S,4S)-3-fluoropiperidin-4-yl)phenol (0.05 g, 68.7% yield)as an off-white solid. LCMS (method P) RT 0.50 min, m/z 196 (M+H⁺); ¹HNMR (400 MHz DMSO-d₆) δ 1.90-1.94 (m, 2H), 2.91-3.05 (m, 3H), 3.24-3.27(m, 1H), 3.59-3.62 (m, 1H), 4.78-4.97 (m, 1H), 6.71-6.76 (m, 2H),6.99-7.06 (m, 2H), 9.27 (s, 1H), 9.36 (s, 1H).

Step K.(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-oneand(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)-ethyl)pyrrolidin-2-one

To a solution of ((3S,4S)-3-fluoropiperidin-4-yl)phenol (0.02 g, 0.1mmol, E-1b from step J) in DMF (2 mL) was added DIPEA (0.05 mL, 0.31mmol) followed by3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one (0.059 g, 0.21mmol, mixture of diastereomers from step B), and the mixture was thenheated to 120° C. in a microwave reactor for 90 min. The mixture wasallowed to cool and then the diastereomeric products were subjected topreparative HPLC (method B) to afford homochiral examples 50 P-3 (2.7mg, 6% yield) and P-4 (8.2 mg, 19.8% yield). Data for P-3(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one:pale yellow solid; LCMS (method N) RT 1.60 min, m/z 401 (M+H⁺); ¹H NMR(400 MHz, methanol-d₄) δ 1.56 (d, J=7.20 Hz, 3H), 1.81-1.85 (m, 2H),2.16-2.22 (m, 1H), 2.42-2.44 (m, 1H), 2.51-2.67 (m, 2H), 3.06-3.09 (m,3H), 3.35-3.40 (m, 2H), 3.70-3.75 (m, 1H), 4.35-4.70 (m, 1H), 5.42 (q,J=7.20 Hz, 1H), 6.74-6.76 (m, 2H), 7.09-7.14 (m, 4H), 7.37-7.41 (m, 2H).Data for P-4(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)-pyrrolidin-2-one:pale yellow solid; LCMS (method N) RT 1.63 min, m/z 401 (M+H⁺); ¹H NMR(400 MHz, methanol-d₄) δ 1.59 (d, J=7.20 Hz, 3H), 1.81-1.84 (m, 2H),2.08-2.16 (m, 2H), 2.42-2.43 (m, 1H), 2.51-2.59 (m, 1H), 2.65-2.72 (m,1H), 2.73-2.81 (m, 1H), 2.92-2.95 (m, 1H), 3.34-3.37 (m, 2H), 3.61-3.66(m, 1H), 4.50-4.71 (m, 1H), 5.43 (q, J=6.80 Hz, 1H), 6.75-6.77 (m, 2H),7.09-7.13 (m, 4H), 7.35-7.38 (m, 2H).

Example 51 (Peak-1, Peak-2, Peak-3, and Peak-4)(S)-3-((R)-3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one,(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one,(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one,and(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

Step A. 1-Benzyl-4-(4-methoxyphenyl)piperidin-4-ol

To a solution of 1-bromo-4-methoxybenzene (5 g, 27 mmol) in THF (100 mL)at −78° C. was added a solution of 1.6 M N-butyl lithium/hexanes (18.4mL, 29.4 mmol), and the reaction mixture was stirred for 1 hr. Then asolution of 1-benzylpiperidin-4-one (4.81 g, 25.4 mmol) in 50 mL of THFwas added. After the addition, the mixture was allowed to warm up to rtand was stirred for 1 h. The reaction was then quenched by the additionof 100 mL of 1.5 M aqueous HCl and the mixture was extracted with 200 mLof ethyl acetate. The organic layer was dried over Na₂SO₄, filtered, andconcentrated under vacuum to yield 7.1 g (72% yield) of1-benzyl-4-(4-methoxyphenyl)piperidin-4-ol. LCMS (method F) RT 2.19 min,81% AP, m/z 298.4 (M+H⁺), ¹H NMR (300 MHz, DMSO-d₆) δ 7.23-7.39 (m8.5H), 6.94 (m, 0.5H), 6.84-6.94 (m, 2H), 4.66 (s, 1H), 3.74 (s, 0.8H),3.72 (s, 3H), 3.32 (s, 2H), 2.50-2.67 (m, 2H), 2.34-2.45 (m, 3H),1.83-1.90 (m, 2H), 1.55 (d, J=11, 2H).

Step B. 1-Benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine

To a solution of 1-benzyl-4-(4-methoxyphenyl)piperidin-4-ol (7 g, 23.5mmol) in DCM (150 mL) was added trifluoroacetic acid (2.68 g, 23.5 mmol)and the reaction mixture was stirred at rt overnight. The mixture wasthen evaporated under reduced pressure and partitioned between 500 mLsaturated aqueous sodium bicarbonate and 500 mL of ethyl acetate. Theorganic layer was separated, dried over Na₂SO₄, filtered, and evaporatedunder reduced pressure to yield1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (5.9 g, 88%yield). LCMS (method F) RT 2.84 min, 100% AP, m/z 280.4 (M+H⁺).

Step C. (±)-rel-(3S,4S)-1-Benzyl-4-(4-methoxyphenyl)piperidin-3-ol

To a suspension of NaBH₄ (2.7 g, 72 mmol) in THF (150 mL) at −10° C. wasadded boron trifluoride etherate (9.1 mL, 72 mmol) and the solution wasstirred for 15 minutes. Then a solution of1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (10 g, 36 mmol)in 100 mL tetrahydrofuran was added and the mixture was stirred for anadditional hour. Next were sequentially added 25 mL of water, 25 mL of10% aqueous sodium hydroxide, 50 mL of ethanol, and 12.8 mL of 30%aqueous hydrogen peroxide (125 mmol) and the final mixture was heated toreflux overnight. The mixture was allowed to cool and was then dilutedwith 200 mL of water and extracted with 300 mL of ethyl acetate. Theorganic layer was separated, dried over Na₂SO₄, filtered, and evaporatedunder reduced pressure. The residue was triturated with diethyl ether toyield 7.5 g (57%)(±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol. LCMS (methodA) RT 2.03 min, 81.5% AP, m/z 298.4 (M+H⁺), ¹H NMR (300 MHz, DMSO-d₆) δppm 7.28-7.35 (m, 5H) 7.14 (d, J=8.69 Hz, 2H) 6.83 (d, J=8.69 Hz, 2H)4.43 (d, J=6.04 Hz, 1H) 3.51 (d, J=19.26 Hz, 4H) 3.33 (s, 3H) 2.97 (dd,J=10.01, 3.59 Hz, 1H) 2.81 (d, J=10.95 Hz, 1H) 2.19-2.29 (m, 1H)1.96-1.98 (m, 1H) 1.78 (t, J=10.20 Hz, 1H) 1.58-1.68 (m, 2H).

Step D. (±)-rel-(3S,4S)-4-(4-Methoxyphenyl)piperidin-3-ol

To a solution of(±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (7 g, 23.5mmol) in methanol (100 mL) was added 10% Pd/C (3.76 g) and the reactionmixture was stirred overnight under a hydrogen atmosphere (balloonpressure). The catalyst was removed by filtration through Celite and thesolvent was evaporated under reduced pressure to give(±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (4.8 g, 89% yield).LCMS (method F) RT 1.485 (61.5% AP) m/z 207.8 (M+H⁺), 1.536 (29.7% AP),m/z 207.8 (M+H⁺); ¹H NMR (DMSO-d6) δ 7.133 (d, J=7, 2H), 6.83 (d, J=7,2H), 4.31 (br s, 1H), 3.7 (s, 3H), 3.02 (m, 1H), 2.86 (d, J=12, 1H),2.45 (m, 1H), 2.22-2.39 (m, 2H), 1.62-1.61 (m, 1H), 1.610-1.46 (m, 1H).

Step E.(±)-rel-3-((3R,4R)-3-Hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (Intermediate 2,450 mg, 1.68 mmol), (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol(313 mg, 1.5 mmol) and triethylamine (23 mL, 16.8 mmol) was stirred at60° C. for 1 h, followed by heating at 85° C. for 1 h, 120° C. for 1 hand at 140° C. for 1 h. The mixture was cooled and then quenched with 40mL of water and extracted with 3×50 mL of chloroform. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated undervacuum. The residue was purified via silica gel chromatography (24 gcolumn, gradient of 0-80% ethyl acetate/petroleum ether) to yield 375 mgof(±)-rel-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-oneas a mixture of four diastereomers. LCMS (method F) RT 1.84 min (74%AP), m/z 395.2 (M+H⁺); ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.31-7.41 (m, 8H)6.86 (d, J=9.07 Hz, 2H) 4.66 (s, 1H) 3.73 (s, 3H) 3.49 (s, 2H) 2.59 (d,J=10.58 Hz, 2H) 2.32-2.47 (m, 3H) 1.89 (td, J=12.65, 4.53 Hz, 2H) 1.56(d, J=11.71 Hz, 2H).

Step F.4-(4-Methoxyphenyl)-1-(1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-3-one

A mixture of DMSO (0.17 mL, 2.46 mmol) and DCM (4 mL) was cooled to −78°C., and oxalyl chloride (0.2 mL, 2.3 mmol) was added dropwise over 2min. Following the addition, the mixture was stirred at the sametemperature for 10 min. To the reaction was then added dropwise(±)-rel-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one(375 mg, 0.95 mmol, mixture of four diastereomers from step E) in DCMover 5 min. The mixture was stirred for 1 h, and then triethylamine (1mL, 7.6 mmol) was added and the mixture was stirred for 15 min, slowlywarmed to rt, and then extracted with 3×40 mL of DCM. The combinedorganic layers were washed with 50 mL of brine, dried over Na₂SO₄,filtered, and concentrated under vacuum to yield 345 mg of4-(4-methoxyphenyl)-1-(1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-3-one(as a mixture of 4 diastereomers), which was used directly in the nextstep. LCMS (method) RT 1.12 min, m/z 393 (M+H⁺), 411 (M+H⁺+18), 1.18min, m/z 393 (M+H⁺).

Step G.3-(3,3-Difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

A mixture of4-(4-methoxyphenyl)-1-(1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-3-one(370 mg, 0.94 mmol) and DCM (5 mL) was cooled to 0° C., followed by thedrop-wise addition of DAST (0.62 mL, 4.7 mmol) over 2 minutes.

The mixture was warmed to rt and stirred overnight. The reaction wasthen quenched with 50 mL of aqueous sodium bicarbonate and extractedwith 3×50 mL of DCM.

The combined organic layers were washed with 50 mL of brine, separated,dried over Na₂SO₄, filtered, and concentrated under vacuum to yield 380mg of3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one(as a mixture of 4 diastereomers), which was used directly in the nextstep. LCMS (method J) RT 1.32 min (29% AP), m/z 397, 478, 1.36 min (45%AP), m/z 415.2 (M+H⁺).

Step H.3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

A mixture of3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one(230 mg, 0.55 mmol) and 4 mL DCM was cooled to −78° C., followed by thedropwise addition of boron tribromide (0.05 mL, 0.55 mmol).

The mixture was then allowed to warm up to rt over 4 h. The reaction wasthen quenched with 50 mL of 10% aqueous sodium bicarbonate and extractedwith 4×50 mL DCM. The combined organic fractions were dried over Na2SO4,filtered, and concentrated. The residue was subjected to preparativeHPLC (method B) to afford 28.1 mg3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-oneas a mixture of 4 diastereomers. LCMS (method N) RT 1.59 min, m/z 401(M+H⁺).

Step I.(S)-3-((R)-3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one,(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one,(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one,and(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

A mixture of 4 diastereomers of3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-onefrom step H (34 mg) was separated via chiral SFC (method K) to yieldhomochiral Examples 51 P-1 (6.8 mg), P-2 (3.7 mg), P-3 (3.7 mg), and P-4(4.5 mg) which include(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one,(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one,(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one,and(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one.The absolute and relative stereochemical configurations were notdetermined. The compounds were arbitrarily designated as P-1, P-2, P-3,and P-4 based on their order of elution during the chiral separation.Data for P-1: ¹H NMR (400 MHz, methanol-d₄) δ=7.19-7.11 (m, 6H),6.76-6.72 (m, 2H), 4.51-4.36 (m, 2H), 3.70 (t, J=8.8 Hz, 1H), 3.30-3.20(m, 2H), 3.16-3.07 (m, 3H), 2.98-2.84 (m, 1H), 2.53 (t, J=1.0 Hz, 1H),2.34 (s, 3H), 2.28-2.13 (m, 2H), 2.03 (s, 1H), 1.88-1.80 (m, 1H); ¹⁹FNMR (methanol-d₄) δ s −102.58, s −103.22, s −115.114, s −115.753; HPLC(method D) RT 8.21 min, 97.5% AP, (method C) RT 8.0 min, 97.6% AP; LCMS(method P) RT 2.37 min, m/z 401 (M+H⁺); chiral SFC (method C-5) RT 5.56min, 100% AP. Data for P-2: ¹H NMR (400 MHz, methanol-d₄) δ=7.18-7.12(m, 6H), 6.77-6.73 (m, 2H), 4.44 (q, J=1.0 Hz, 2H), 3.68 (t, J=8.8 Hz,1H), 3.41-3.35 (m, 1H), 3.31-3.20 (m, 2H), 3.01-2.83 (m, 3H), 2.72-2.60(m, 1H), 2.34 (s, 3H), 2.27-2.11 (m, 2H), 2.08-1.96 (m, 1H), 1.82 (tdd,J=2.5, 5.0, 13.1 Hz, 1H); ¹⁹F NMR (methanol-d₄) δ s −102.461, s−103.102, s −114.549, s −115.189; HPLC (method D) RT 8.33 min, 98.3% AP,(method C) RT 8.21 min, 98.2% AP; LCMS (method P) RT 2.37 min, m/z 401(M+H⁺); chiral SFC (method C-5) RT 7.39 min, 99.7% AP. Data for P-3: ¹HNMR (400 MHz, methanol-d₄) δ ppm 1.78-1.87 (m, 1H) 1.98-2.08 (m, 1H)2.14-2.27 (m, 2H) 2.34 (s, 3H) 2.60-2.72 (m, 1H) 2.83-3.01 (m, 3H)3.21-3.31 (m, 2H) 3.35-3.41 (m, 1H) 3.68 (t, J=8.78 Hz, 1H) 4.44 (q,J=1.00 Hz, 2H) 6.72-6.76 (m, 2H) 7.11-7.18 (m, 6H); ¹⁹F NMR (377 MHz,methanol-d₄) δ s −102.457, s −103.097, s −114.554, s −115.194; HPLC(method D) RT 8.34 min, 98.6% AP, (method C) RT 8.21 min, 99% AP; LCMS(method P) RT 2.29 min, m/z 401 (M+H⁺); chiral SFC (method C-5) RT 10.1min, 97.8% AP. Data for P-4: ¹H NMR (400 MHz, methanol-d₄) δ ppm1.80-1.90 (m, 1H) 2.03 (s, 1H) 2.13-2.29 (m, 2H) 2.34 (s, 3H) 2.53 (t,J=1.00 Hz, 1H) 2.85-3.00 (m, 1H) 3.07-3.18 (m, 3H) 3.20-3.31 (m, 2H)3.71 (t, J=8.78 Hz, 1H) 4.44 (q, J=1.00 Hz, 2H) 6.73-6.78 (m, 2H)7.12-7.19 (m, 6H); ¹⁹F NMR (methanol-d₄) δ s −102.579, s −103.217, s−115.087, s −115.726; HPLC (method D) RT 8.2 min, 96.4% AP, (method C)RT 8.0 min, 96.5% AP; LCMS (method P) RT 2.21 min, m/z 401 (M+H⁺);chiral SFC (method C-5) RT 13.6 min, 100% AP.

Example 52 (Peak-1, Peak-2, Peak-3, and Peak-4)(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one,(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)-pyrrolidin-2-one,(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one,and(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

Step A. tert-Butyl 4-(4-(benzyloxy)phenyl)-3-oxopiperidine-1-carboxylate

To a solution of DMSO (3.7 mL, 52 mmol) in 50 mL of DCM under nitrogenat −78° C. was added oxalyl chloride (4.45 mL, 51 mmol). The mixture wasstirred for 10 minutes after the completion of the addition. Then asolution of (±)-rel-(3S,4S)-tert-butyl4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (from Example50, step D, 6.5 g, 17 mmol) in 50 mL of DCM was added and the mixturewas stirred in the cold for a further 90 minutes. The reaction was thenquenched by the addition of 11.8 mL of triethylamine (85 mmol) andallowed to warm up to rt. The mixture was then partitioned between 200mL brine and 200 mL DCM. The layers were separated, and the organiclayer was dried over Na₂SO₄, filtered, and concentrated.

The residue was subjected to column chromatography on 48 g of basicalumina eluting with 8% ethyl acetate/hexanes to afford 4.7 g (67%) ofracemic tert-butyl4-(4-(benzyloxy)phenyl)-3-oxopiperidine-1-carboxylate. LCMS (method F)RT 2.376 min, m/z 381.2 (M+); chiral SFC (method G) RT 4.54 min (46.9%AP, 4.93 min (49.7% AP). ¹H NMR (400 MHz, DMSO-d₆) δ 7.30-7.40 (m, 5H),7.07 (d, J=7 Hz, 2H) 6.94 (d, J=7), 2H; 5.08 (s, 2H), 4.10 (d, J=17.6,1H), 3.97 (d, J=17.6, 1H), 3.77 (m, 2H), 3.43 (br s, 1H), 2.16 (m, 2H),1.42 (s, 9H).

Step B. tert-Butyl4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine-1-carboxylate

To a solution of tert-butyl4-(4-(benzyloxy)phenyl)-3-oxopiperidine-1-carboxylate (4.7 g, 12.3 mmol)in 100 mL DCM at 0° C. was added DAST (8.1 mL, 62 mmol) and the reactionmixture was stirred for 1 h. It was then allowed to warm to rt andpartitioned between saturated sodium bicarbonate and 200 mL of DCM. Thelayers were separated and the organic phase was dried over Na₂SO₄,filtered, and concentrated to afford 4.2 g (68%) of racemic tert-butyl4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine-1-carboxylate. LCMS(method P) RT 1.16 min, m/z 348.1 (M-t-butyl+H)⁺.

Step C. 4-(4-(Benzyloxy)phenyl)-3,3-difluoropiperidine

To a solution of t-butyl4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine-1-carboxylate (5.2 g,12.9 mmol) in MeOH (100 mL) was added 4 M HCl/dioxane (32.2 mL, 130mmol) and the reaction mixture was stirred at rt for 5 h. The mixturewas then evaporated under reduced pressure, and the residue was dilutedwith a saturated sodium bicarbonate solution and extracted with 200 mLof ethyl acetate. The layers were separated and the organic phase wasdried over Na₂SO₄, filtered, and concentrated under vacuum. The residuewas subjected to preparative HPLC (method C) to afford 2.5 grams (63%)of racemic 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine. LCMS (methodF) RT 2.044 min, m/z 304 (M+H⁺); ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.31-7.48 (m, 5H) 7.21 (d, J=8.53 Hz, 2H) 6.98 (d, J=9.04 Hz, 2H) 5.10(s, 2H) 3.05-3.20 (m, 2H) 2.98 (d, J=13.05 Hz, 1H) 2.74-2.87 (m, 1H)2.60 (t, J=11.55 Hz, 1H) 1.88-2.00 (m, 4H) 1.72 (d, J=13.05 Hz, 1H), ¹⁹FNMR (377 MHz, DMSO-d₆) δ −102.276, −102.900, −115.135, −115.759.

Step D.3-(4-(4-(Benzyloxy)phenyl)-3,3-difluoropiperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

To a mixture of 3-bromo-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one(0.51 g, 1.8 mmol, Intermediate 6) and4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine (0.3 g, 1 mmol, from stepC) was added triethylamine (0.69 mL, 4.9 mmol) and the resulting mixturewas heated in a sealed tube at 120° C. for 1 h. The reaction mixture wasallowed to cool and then diluted with water and the mixture wasextracted with ethyl acetate. The organic layer was separated, washedwith brine, dried over Na₂SO₄, filtered, and concentrated. The residue(0.45 grams, 64%, mixture of 4 diastereoisomers) was used directly inthe next step without further purification, LCMS (method P) RT 1.19 min,m/z 509 (M+H⁺).

Step E.3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

To a stirred solution of3-(4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one(0.45 g, 0.89 mmol, mixture of diastereomers from step D) in MeOH (8 mL)at rt was added 0.56 g of 10% Pd/C and the reaction mixture was stirredat rt under a hydrogen atmosphere overnight. The catalyst was removed byfiltration through Celite and the solvent was removed in vacuo. Theresidue was subjected to HPLC purification (method E) to yield 200 mg of3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-oneas a mixture of four diastereoisomers.

Step F.(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one,(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)-pyrrolidin-2-one,(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one,and(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

The mixture of diastereomers of3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one(0.1 g, 0.239 mmol) from step E was subjected to chiral SFC purificationto afford homochiral Examples 52 P-1 (12.8 mg), P-2 (13.7 mg), P-3 (6.7mg), and P-4 (13.1 mg) which include(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one,(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)-pyrrolidin-2-one,(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one,and(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one.The absolute and relative stereochemical configurations were notdetermined. The compounds were arbitrarily designated as P-1, P-2, P-3,and P-4 based on their order of elution during the chiral separation.Data for P-1: yellow solid; LCMS (method F) RT 2.05 min, 100% AP, m/z419.2 (M+H⁺); HPLC (method A) RT 8.45 min 98.2% AP, (method B) RT 8.56min, 97.8% AP; chiral SFC (method C-5) RT 4.52 min, 100% AP; ¹H NMR (400MHz, methanol-d₄) δ 7.23 (t, J=7.8 Hz, 1H), 7.15 (d, J=8.0 Hz, 2H),7.03-6.93 (m, 2H), 6.75 (d, J=8.5 Hz, 2H), 4.52-4.36 (m, 2H), 3.71 (t,J=8.8 Hz, 1H), 3.31-3.23 (m, 3H), 3.19-3.12 (m, 2H), 3.11-3.07 (m, 1H),3.00-2.83 (m, J=13.2, 4.7, 4.7 Hz, 1H), 2.53 (t, J=11.0 Hz, 1H), 2.26(d, J=1.5 Hz, 3H), 2.25-2.21 (m, 1H), 2.20-2.13 (m, 1H), 2.11-1.99 (m,1H), 1.89-1.78 (m, 1H); ¹⁹F NMR (377 MHz, chloroform-d) 6-133.04 (s,1F), −133.68 (s, 1F), −145.26 (s, 1F), −145.90 (s, 1F), −147.99 (s, 1F).Data for P-2: yellow solid; LCMS (method F) RT 2.05 min, 95.8% AP, m/z419.2 (M+H⁺); HPLC (method A) RT 8.64 min 97.8% AP, (method B) RT 8.71min, 97.6% AP; chiral SFC (method C-5) RT 6.35 min, 95.4% AP; ¹H NMR(400 MHz, methanol-d₄) δ 7.23 (t, J=7.8 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H),7.04-6.92 (m, 2H), 6.81-6.70 (m, 2H), 4.53-4.35 (m, 2H), 3.69 (t, J=8.8Hz, 1H), 3.46-3.35 (m, 2H), 3.31-3.22 (m, 2H), 3.04-2.94 (m, 2H),2.93-2.83 (m, 2H), 2.74-2.58 (m, 1H), 2.28-2.25 (m, 3H), 2.25-2.15 (m,2H), 1.87-1.78 (m, 1H); ¹⁹F NMR (377 MHz, chloroform-d) 6-132.68 (s,1F), −133.32 (s, 1F), −144.55 (s, 1F), −145.19 (s, 1F), −147.96 (s, 1F).Data for P-3: yellow solid; LCMS (method F) RT 2.05 min, 92.1% AP, m/z419.2 (M+H⁺); HPLC (method A) RT 8.70 min 97.3% AP, (method B) RT 8.64min, 97.1% AP; chiral SFC (method C-5) RT 8.81 min, 98.2% AP; ¹H NMR(400 MHz, methanol-d₄) δ 7.24 (t, J=7.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H),7.05-6.91 (m, 2H), 6.81-6.68 (m, 2H), 4.45 (dd, J=30.5, 14.5 Hz, 2H),3.69 (t, J=8.8 Hz, 1H), 3.46-3.36 (m, 2H), 3.31-3.22 (m, 2H), 3.05-2.94(m, 2H), 2.93-2.81 (m, 2H), 2.75-2.56 (m, J=8.0, 8.0 Hz, 1H), 2.27 (d,J=1.5 Hz, 3H), 2.25-2.11 (m, 1H), 2.05 (dd, J=13.3, 8.3 Hz, 1H),1.90-1.76 (m, 1H); ¹⁹F NMR (377 MHz, chloroform-d) 6-132.68 (s, 1F),−133.32 (s, 1F), −144.53 (s, 1F), −145.17 (s, 1F), −147.94 (s, 1F). Datafor P-4: yellow solid; LCMS (method F) RT 2.05 min, 94.5% AP, m/z 419.2(M+H⁺); HPLC (method A) RT 8.45 min 96.9% AP, (method B) RT 8.56 min,97.0% AP; chiral SFC (method C-5) RT 12.13 min, 99.4% AP; ¹H NMR (400MHz, methanol-d₄) δ 7.23 (t, J=7.8 Hz, 1H), 7.19-7.11 (m, J=8.5 Hz, 2H),7.04-6.92 (m, 2H), 6.81-6.71 (m, J=8.5 Hz, 2H), 4.53-4.35 (m, 2H), 3.72(t, J=8.8 Hz, 1H), 3.32-3.22 (m, 2H), 3.20-3.07 (m, 3H), 3.04-2.82 (m,1H), 2.53 (t, J=11.3 Hz, 1H), 2.26 (d, J=1.5 Hz, 3H), 2.25-2.12 (m, 2H),2.12-2.01 (m, 2H), 1.92-1.78 (m, 1H); ¹⁹F NMR (377 MHz, chloroform-d)6-133.04 (s, 1F), −133.68 (s, 1F), −145.25 (s, 1F), −145.89 (s, 1F),−147.99 (s, 1F).

Example 53 (Peak-1 and Peak-2)3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)-benzyl)pyrrolidin-2-one

Step A. 2,4-Dibromo-N-(4-(trifluoromethyl)benzyl)butanamide

To a solution of (4-(trifluoromethyl)phenyl)methanamine (3 g, 17 mmol)in diethyl ether (60 mL) under nitrogen at 0° C. was added2,4-dibromobutanoyl chloride (2.3 mL, 17 mmol) and the reaction mixturewas stirred for 1 h at rt. The mixture was then diluted with water andextracted with 200 mL of ethyl acetate. The organic layer was dried overNa₂SO₄, filtered, and evaporated under reduced pressure to afford2,4-dibromo-N-(4-(trifluoromethyl)benzyl)-butanamide (6.5 g, 87%). LCMS(method F) RT 2.01 min, m/z 434.8, 483.8; ¹H NMR (400 MHz, DMSO-d₆) δppm 2.39-2.47 (m, 2H) 3.50-3.67 (m, 2H) 4.41 (dd, J=13.05, 6.02 Hz, 2H)4.59-4.64 (m, 1H) 7.49 (d, J=7.53 Hz, 2H) 7.71 (d, J=8.03 Hz, 2H) 9.06(s, 1H).

Step B. 3-Bromo-1-(4-(trifluoromethyl)benzyl)pyrrolidin-2-one

To a suspension of 2,4-dibromo-N-(4-(trifluoromethyl)benzyl)butanamide(6.8 g, 16.9 mmol) in tetrahydrofuran (200 mL) was added NaH (1.35 g, 34mmol) and the reaction was stirred at rt for 4 h. The reaction mixturewas then diluted with water and twice extracted with 30 mL of ethylacetate. The combined organic layers were dried over Na₂SO₄, filtered,and evaporated to dryness. The residue was purified by silica gelchromatography eluting with 0-40% ethyl acetate/hexanes to afford 2.8 gof 3-bromo-1-(4-(trifluoromethyl)benzyl)pyrrolidin-2-one (48%). LCMS(method Q) RT 0.90 min, m/z 322.1 (M+H⁺); ¹H NMR (400 MHz, chloroform-d)δ 12.39 (d, J=8.0 Hz, 2H), 12.16 (d, J=8.0 Hz, 2H), 9.46-9.38 (m, 1H),9.25 (d, J=1.8 Hz, 2H), 8.27-8.17 (m, 1H), 7.99 (s, 1H), 7.43-7.31 (m,1H), 7.14-7.05 (m, 1H).

Step C. (R)-4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine and(S)-4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine

Racemic 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine (2.2 g, 7.3 mmol,from Example 52, step C) was submitted to chiral separation (method H-4)and the chirally pure fractions were collected and evaporated underreduced pressure to give E1 (850 mg, 2.77 mmol, 38.3% yield) and E2 (780mg, 2.55 mmol, 35.1% yield)(R)-4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine and(S)-4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine (absoluteconfiguration not assigned). Data for E-1: LCMS (method F) RT 2.16 min,m/z 304 (M+H⁺); Chiral HPLC (method H-3) RT 11.1 min, 100% AP; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.72 (d, J=13.55 Hz, 1H) 1.94 (dd, J=12.55,4.02 Hz, 1H) 2.60 (t, J=12.05 Hz, 1H) 2.74-2.88 (m, 1H) 2.98 (d, J=12.55Hz, 1H) 3.04-3.20 (m, 2H) 5.10 (s, 2H) 6.95-7.02 (m, 2H) 7.21 (d, J=8.53Hz, 2H) 7.30-7.50 (m, 5H); ¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm −102.275,−102,900, −115.135, −115.759. Data for E-2: LCMS (method F) RT 2.16 min,m/z 304 (M+H⁺); Chiral HPLC (method H-3) RT 18.28 min, 99.7% AP; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.72 (d, J=12.55 Hz, 1H) 1.94 (dd, J=13.05,4.02 Hz, 1H) 2.55-2.64 (m, 1H) 2.74-2.88 (m, 1H) 2.98 (d, J=13.05 Hz,1H) 3.05-3.20 (m, 2H) 5.10 (s, 2H) 6.95-7.00 (m, 2H) 7.21 (d, J=8.53 Hz,2H) 7.30-7.49 (m, 5H): ¹⁹F NMR (400 MHz, DMSO-d₆) δ ppm −102.276,−102-900, −115.134, −115.748.

Step D. 4-(3,3-Difluoropiperidin-4-yl)phenol

A mixture of 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine (E-2 fromStep C, above, 1 g, 3.3 mmol) and methanol (15 mL) was flushed withnitrogen, followed by the addition of 10% Pd/C (0.7 g). The reactionmass then stirred overnight at rt under 160 psi of hydrogen pressure ina 100 mL autoclave. The catalyst was then removed by filtration throughCelite and the filtrate was concentrated under vacuum. A yield of 0.65 g(78%) of E-2a 4-(3,3-difluoropiperidin-4-yl)phenol was obtained. LCMS(method Q) RT 0.47 min, m/z 214.1 (M+H⁺).

Step E.3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)benzyl)pyrrolidin-2-one

A mixture of 4-(3,3-difluoropiperidin-4-yl)phenol (200 mg, 0.94 mmol,E-2a from step D), 3-bromo-1-(4-(trifluoromethyl)benzyl)pyrrolidin-2-one(604 mg, 1.9 mmol), triethylamine (0.65 mL, 4.7 mmol), and 2 mL of DMFwas heated in a microwave reactor at 120° C. for 1 h. The cooledreaction mixture was partitioned between water and 30 mL of ethylacetate, and the aqueous phase was again extracted with 30 mL of ethylacetate. The combined organic layers were dried over Na₂SO₄, filtered,and concentrated to afford 150 mg of3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)-benzyl)pyrrolidin-2-one(0.33 mmol, 35%, 2 diastereoisomers) which was purified and separated instep F. LCMS (method J) RT 0.8 min (60% AP), m/z 455.4 (M+H⁺).

Step F.3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)-benzyl)pyrrolidin-2-one

The product3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)-benzyl)pyrrolidin-2-one(150 mg, 0.33 mmol), from step E was separated via SFC (method C-7) togive the separated diastereomers, which were individually purified viapreparative HPLC (method B) to give homochiral Examples 53 P-1 (40.8 mg)and P-2 (39.3 mg). The products differ at the lactam 3-positionstereocenter; however, the relative stereochemical configurations werenot determined. Data for P-1: pale yellow solid. LCMS (method N) RT 1.70min (99.7% AP), m/z 455.0 (M+H⁺); ¹H NMR (400 MHz, methanol-d₄) δ=7.69(d, J=8.5 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H),6.80-6.71 (m, 2H), 4.58 (d, J=16.6 Hz, 2H), 3.75 (s, 1H), 3.30-3.25 (m,2H), 3.23-3.09 (m, 3H), 3.02-2.85 (m, 1H), 2.59-2.50 (m, 1H), 2.33-2.03(m, 3H), 1.91-1.80 (m, 1H). ¹⁹F NMR (400 MHz, methanol-d₄) δ −64.073,−102.629, −103.268, −115.125, −115.764. Data for P-2: pale yellow solid.LCMS (method N) RT 1.71 min (99.7% AP), m/z 455.0 (M+H⁺); ¹H NMR (400MHz, methanol-d₄) δ=7.69 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.15(d, J=8.0 Hz, 2H), 6.79-6.72 (m, 2H), 4.65-4.52 (m, 2H), 3.72 (t, J=9.0Hz, 1H), 3.47-3.38 (m, 1H), 3.31-3.26 (m, 1H), 3.03-2.84 (m, 3H),2.74-2.61 (m, 1H), 2.31-2.01 (m, 3H), 1.88-1.80 (m, 1H). ¹⁹F NMR (400MHz, methanol-d₄) δ −64.074, −102.511, −103.151, −114.583, −115.225.

Example 54 (Peak-1, Peak-2, Peak-3, and Peak-4)(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one,(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one,(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one,and(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one

Step A. (3S,4S)-4-(4-Methoxyphenyl)piperidin-3-ol and(3R,4R)-4-(4-methoxyphenyl)piperidin-3-ol

Racemic (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (2.6 g, 12.54mmol, from Example 51, step D) was subjected to SFC chiral purification(Method H-1), which gave enantiomers E-1 (680 mg) and E-2 (720 mg),(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol and(3R,4R)-4-(4-methoxyphenyl)piperidin-3-ol (absolute configurations notassigned). Data for E-1, 1st eluting isomer: Chiral SFC (method H) RT2.57 min; 98% AP; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.13 (d, J=9 Hz, 2H)6.84 (d, J=9 Hz, 2H) 4.43 (br. s., 1H) 3.72 (s, 3H) 3.43 (d, J=10.54 Hz,2H) 3.08 (dd, J=11.80, 4.77 Hz, 1H) 2.92 (d, J=12.05 Hz, 1H) 2.28-2.39(m, 2H) 1.47-1.68 (m, 2H). Data for E-2, 2nd eluting isomer: Chiral SFC(method H) RT 3.18 min; 94.3% AP; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.13(d, J=9 Hz, 2H) 6.85 (d, J=8 Hz, 2H) 4.58 (br. s., 1H) 3.72 (s, 3H) 3.43(br d, 3H) 3.11 (m, 2H) 2.61 (m, 1H) 2.28-2.39 (m, 2H) 1.47-1.68 (m,2H).

Step B.1-(4-Fluorobenzyl)-3-(trans-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one

To a mixture of 3-bromo-1-(4-fluorobenzyl)pyrrolidin-2-one (Intermediate1, 200 mg, 0.74 mmol), trans-4-(4-methoxyphenyl)piperidin-3-ol (152 mg,0.74 mmol, E-2 from step A) and acetonitrile (15 mL) was addedtriethylamine (0.5 mL, 3.7 mmol) and the resulting mixture was heated at100° C. for 1 h. The reaction was then diluted with water and extractedwith ethyl acetate (100 mL). The layers were separated, and the organiclayer was dried over Na₂SO₄, filtered, and evaporated under reducedpressure to afford1-(4-fluorobenzyl)-3-(trans-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one(mixture of 2 diastereomers, 320 mg, 73.% yield). LCMS (method F) RT1.706 min (67% AP) m/z 399.4 (M+H⁺).

Step C.1-(1-(4-Fluorobenzyl)-2-oxopyrrolidin-3-yl)-4-(4-methoxyphenyl)piperidin-3-one

To a mixture of DMSO (0.14 mL, 2 mmol) and DCM (20 mL) at −78° C. undernitrogen was added oxalyl chloride (0.18 mL, 2 mmol) and the reactionmixture was stirred for 10 min. Then1-(4-fluorobenzyl)-3-(trans-3-hydroxy-4-(4-methoxyphenyl)-piperidin-1-yl)pyrrolidin-2-one(320 mg, 0.8 mmol) was added and the reaction was stirred for one hourat same temperature. Triethylamine (0.56 mL, 4 mmol) was then added, andthe reaction mixture was allowed to warm to rt. The mixture was thenpartitioned between water (100 mL) and DCM (200 mL). The organic layerwas separated, dried over Na₂SO₄, filtered, and evaporated under reducedpressure to give afford the crude product, which was taken on to step Dwithout further purification. LCMS (method Q) RT 0.68 min (47% AP), m/z397.1 (M+H⁺).

Step D.3-(3,3-Difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one

To a solution of1-(1-(4-fluorobenzyl)-2-oxopyrrolidin-3-yl)-4-(4-methoxyphenyl)piperidin-3-one(350 mg, 0.88 mmol) in 15 mL of DCM at −10° C. was added DAST (0.58 mL,4.4 mmol) and the reaction was stirred under nitrogen for 1 h. Themixture was then diluted with a saturated sodium bicarbonate solution(100 mL) and extracted with 250 mL of DCM. The organic layer wasseparated, dried over Na2SO4, filtered, and evaporated under reducedpressure to yield3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one(mixture of diastereomers), which was used in step E without furtherpurification. LCMS (method F) RT 1.939 min, 55.8% AP, m/z 381.2, 471.2.

Step E.3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one

To a solution of3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one(200 mg, 0.48 mmol, mixture of diastereomers from step D) in DCM (15 mL)at −10° C. was added boron tribromide (0.05 mL, 0.48 mmol) and thereaction mixture was stirred under nitrogen for one hour. The mixturewas then diluted with a satd. sodium bicarbonate solution and extractedwith 100 mL of DCM. The organic layer was separated, dried over Na₂SO₄,filtered, and evaporated under reduced pressure. The residue waspurified via preparative HPLC (method D) to yield3-(3,3-difluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one(mixture of 4 diastereomers, 34 mg, 17% yield). LCMS (method N) RT 1.497min, m/z 405.0 (M+H⁺).

Step F.(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one,(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one,(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one,and(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one

The diastereomeric mixture of3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one(32 mg, 0.08 mmol, from step E) was purified by SFC (method C-8) toobtain homochiral Examples 54 P-1 (5.2 mg), P-2 (5.2 mg), P-3 (5.4 mg),and P-4 (5.4 mg),(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one,(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one,(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one,and(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one.The absolute and relative stereochemical configurations were notdetermined. The compounds were arbitrarily designated as P-1, P-2, P-3,and P-4 based on their order of elution during the chiral separation.The presence of 4 instead of 2 diastereoisomers implies racemization ofthe starting homochiral piperidine during the course of the synthesis.Data for P-1: HPLC (method D) RT 7.87 min, 95.8% AP, (method A) RT 7.58min, 97.5% AP; LCMS (method F) RT 2.05 min, 100% AP, m/z 405.0 (M+H⁺);chiral SFC (method C-5) RT 4.77 min; ¹H NMR (400 MHz, methanol-d₄) δ ppm7.32 (dd, J=8.78, 5.27 Hz, 2H) 7.06-7.17 (m, 4H) 6.72-6.77 (m, 2H)4.40-4.53 (m, 2H) 3.71 (t, J=8.78 Hz, 1H) 3.22-3.31 (m, 2H) 3.07-3.18(m, 3H) 2.85-2.99 (m, 1H) 2.52 (t, J=11.29 Hz, 1H) 1.99-2.31 (m, 3H)1.84 (ddt, J=13.30, 4.77, 2.26, 2.26 Hz, 1H). Data for P-2: HPLC (methodD) RT 7.89 min, 100% AP, (method A) RT 7.77 min, 95.1% AP; LCMS (methodF) RT 2.04 min, 100% AP, m/z 405.0 (M+H⁺); chiral SFC (method C-5) RT6.6 min; ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.31 (dd, J=8.78, 5.27 Hz,2H) 7.06-7.17 (m, 4H) 6.75 (d, J=8.53 Hz, 2H) 4.47 (q, J=15.06 Hz, 2H)3.68 (t, J=9.04 Hz, 1H) 3.35-3.42 (m, 1H) 3.22-3.30 (m, 1H) 2.82-3.02(m, 3H) 2.59-2.74 (m, 1H) 1.98-2.28 (m, 3H) 1.82 (ddt, J=13.18, 4.64,2.38, 2.38 Hz, 1H). Data for P-3: HPLC (method D) RT 7.99 min, 100% AP,(method A) RT 7.77 min, 96.3% AP; LCMS (method F) RT 2.04 min, 100% AP,m/z 405.0 (M+H⁺); chiral SFC (method C-5) RT 7.25 min; ¹H NMR (400 MHz,methanol-d₄) δ ppm 7.31 (dd, J=8.78, 5.27 Hz, 2H) 7.06-7.17 (m, 4H)6.72-6.78 (m, 2H) 4.40-4.53 (m, 2H) 3.68 (t, J=9.04 Hz, 1H) 3.34-3.43(m, 1H) 3.21-3.30 (m, 1H) 2.77-3.01 (m, 3H) 2.60-2.72 (m, 1H) 1.98-2.29(m, 3H) 1.82 (ddt, J=13.30, 4.77, 2.26, 2.26 Hz, 1H). Data for P-4: HPLC(method A) RT 7.58 min, 96.9% AP; LCMS (method F) RT 2.04 min, 100% AP,m/z 405.0 (M+H⁺); chiral SFC (method C-5) RT 10.3 min; ¹H NMR (400 MHz,methanol-d₄) δ ppm 7.32 (dd, J=8.78, 5.27 Hz, 2H) 7.06-7.17 (m, 4H) 6.75(d, J=8.53 Hz, 2H) 4.39-4.54 (m, 2H) 3.71 (t, J=8.78 Hz, 1H) 3.24-3.30(m, 1H) 3.07-3.18 (m, 3H) 2.85-2.99 (m, 1H) 2.52 (t, J=11.29 Hz, 1H)1.98-2.30 (m, 3H) 1.84 (ddt, J=13.36, 4.83, 2.45, 2.45 Hz, 1H).

Example 55 (Peak-1, Peak-2, Peak-3, and Peak-4)(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one,(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one,(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one,and(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one

Step A. (3R,4R)-tert-Butyl3-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate

To a solution of (3R,4R)-tert-butyl3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (490 mg, 1.67mmol, procedure from WO 2000/63173) in DMF (6 mL) was added K₂CO₃ (577mg, 4.2 mmol) followed by methyl iodide (0.52 mL, 8.4 mmol) at rt. Themixture was stirred at rt for 18 h. It was then diluted with 50 mL ethylacetate and the solids were removed by filtration. The solvent was thenevaporated under vacuum and the residue was purified via silica gelchromatography (hexanes-100% EtOAc) to yield (3R,4R)-tert-butyl3-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate (450 mg, 88%yield). LCMS (method T) RT 3.068 min, m/z 306.3 (M−H)⁻; ¹H NMR (500 MHz,chloroform-d) δ 7.15 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H),4.40-4.30 (m, 1H), 4.25-4.05 (m, 1H), 3.78 (s, 3H), 3.64-3.52 (m, 1H),2.77-2.66 (m, 1H), 2.65-2.51 (m, 1H), 2.45 (br. s., 1H), 2.26-2.10 (m,1H), 1.76 (d, J=2.7 Hz, 1H), 1.71-1.60 (m, 1H), 1.48 (s, 9H).

Step B. tert-Butyl 4-(4-methoxyphenyl)-3-oxopiperidine-1-carboxylate

To a solution of (3R,4R)-tert-butyl3-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate (180 mg, 0.59mmol) in DCM (3 mL) at 0° C. under N₂ was added Dess-Martin Periodinane(373 mg, 0.88 mmol). The mixture was allowed to warm to rt and stirredfor 3 h. The reaction mixture was directly purified via silica gelchromatography eluting with 30% EtOAc in hexanes to afford tert-butyl4-(4-methoxyphenyl)-3-oxopiperidine-1-carboxylate (155 mg, 87% yield).Subsequent results revealed that the 4R stereochemistry is lost in thisreaction and the racemic product was obtained. ¹H NMR (500 MHz,chloroform-d) δ 7.09-7.03 (m, 2H), 6.93-6.87 (m, 2H), 4.24 (d, J=18.0Hz, 1H), 4.11-4.02 (m, 1H), 3.80 (s, 3H), 3.61 (dd, J=11.9, 5.6 Hz, 1H),3.56-3.46 (m, 1H), 2.34-2.16 (m, 2H), 1.50 (s, 9H).

Step C. tert-butyl3,3-difluoro-4-(4-methoxyphenyl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4-methoxyphenyl)-3-oxopiperidine-1-carboxylate (90 mg, 0.3 mmol, fromstep B) in DCM (5 mL) at −78° C. under N₂ was added DAST (0.16 mL, 1.18mmol). The mixture was stirred from −78° C. to rt over 1 h, then allowedto stand in the refrigerator overnight. It was then concentrated andtert-butyl 3,3-difluoro-4-(4-methoxyphenyl)piperidine-1-carboxylate (65mg, 67.4% yield) was isolated which was used without furtherpurification. LCMS (method U) m/z 350.2 (M+Na); ¹H NMR (500 MHz,chloroform-d) δ 7.39 (d, J=8.7 Hz, 2H), 6.95-6.86 (m, 3H), 4.10 (br. s.,2H), 3.83 (s, 3H), 3.82 (s, 1H), 3.64-3.58 (m, 2H), 3.06-2.93 (m, 1H),2.57-2.45 (m, 2H), 1.50 (s, 9H).

Step D. 3,3-Difluoro-4-(4-methoxyphenyl)piperidine trifluoroacetate

To a solution of (R)-t-butyl3,3-difluoro-4-(4-methoxyphenyl)piperidine-1-carboxylate (65 mg, 0.2mmol) in DCM (0.8 mL) was added TFA (0.4 mL, 5.2 mmol) at rt. Themixture was stirred for 2 h, then concentrated to dryness in vacuo toafford crude 3,3-difluoro-4-(4-methoxyphenyl)piperidine trifluoroacetate(67.8 mg, 0.2 mmol, 100% yield), which was used in step G withoutfurther purification.

Step E.3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one

To a solution of 3,3-difluoro-4-(4-methoxyphenyl)piperidinetrifluoroacetate (67 mg, 0.2 mmol) in DMF (0.8 mL) was added3-bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (from Example 49,step C, 96 mg, 0.35 mmol) and DIPEA (0.1 mL, 0.6 mmol). The mixture wasstirred at rt for 18 h, then raised to 80° C. for 2 h. The mixture wascooled, the solvent was removed under vacuum and the residue waspurified via silica gel chromatography, eluting with a gradient from 0to 100% ethyl acetate in hexanes to yield 62 mg of3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one(along with 20 mg of the sideproduct,1-(3-fluoro-4-methylphenyl)-3-hydroxypyrrolidin-2-one). LCMS (method U)RT 3.755 min, m/z 419.3 (M+H⁺); ¹H NMR (500 MHz, chloroform-d) δ 7.51(d, J=11.9, 2H), m 7.26-7.26 (3H), m 7.20 (1H), 6.90 (d, J=8.7) 3.82 (s,3H), 3.65-3.78 (m, 3H), 3.2-3.45 (m, 3H), 2.87-3.00 (m, 1H), 2.72-2.85(m, 0.4H), 2.65 (t, 0.5H), 2.37-2.48 (m, 1H), 2.27 (s, 3H), 2.1-2.25 (m,2H), 1.87-1.95 (m, 1H). Chiral HPLC (method A-2) revealed that thechirality present in the starting material for step A had been lost.

Step F.(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one,(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one,(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one,and(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one

To a solution of3-(3,3-difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one(62 mg, 0.15 mmol) in DCM (0.8 mL) at −78° C. under N₂ was added borontribromide (0.04 mL, 0.44 mmol). The reaction was warmed to rt andstirred for a further 2 h. It was then quenched with several drops ofEtOH, and 50 mL of EtOAc was added. After stirring at rt for 1 h, thesolid was removed by filtration and washed with MeOH. The filtrates werecombined and concentrated. The residue was purified via silica gelchromatography eluting with a gradient of 0 to 10% MeOH in EtOAc to givea mixture containing all four diastereomers, which were separated viachiral HPLC (method A-2) to give homochiral Examples 55 P-1, P-2, P-3,and P-4,(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one,(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one,(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one,and(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one.The absolute and relative stereochemical configurations were notdetermined. The compounds were arbitrarily designated as P-1, P-2, P-3,and P-4 based on their order of elution during the chiral separation.Data for P-1: 7.3 mg; LCMS (method U) RT 2.19 min (82% AP), m/z 405.1,427.3 (M+H⁺, M+Na⁺); chiral HPLC (method A-3) RT 6.28 min, 98.1% AP; ¹HNMR (500 MHz, chloroform-d) δ 7.49 (dd, J=11.8, 1.8 Hz, 1H), 7.26 (d,J=1.7 Hz, 1H), 7.24-7.16 (m, 3H), 6.83 (d, J=8.4 Hz, 2H), 3.84-3.71 (m,3H), 3.37 (t, J=9.2 Hz, 1H), 3.31-3.22 (m, 1H), 3.14 (d, J=10.8 Hz, 1H),3.00-2.88 (m, 1H), 2.87-2.77 (m, 1H), 2.50-2.40 (m, 1H), 2.28 (s, 3H),2.25-2.11 (m, 3H), 1.94-1.86 (m, 1H). Data for P-2: 4.4 mg; LCMS (methodU) RT 2.19 min (86% AP), m/z 405.2, 427.2 (M+H⁺, M+Na⁺); chiral HPLC(method A-3) RT 8.77 min, 78.4% AP; ¹H NMR (500 MHz, chloroform-d) δ7.50 (dd, J=11.9, 2.1 Hz, 1H), 7.28-7.24 (m, 1H), 7.24-7.15 (m, 3H),6.85 (d, J=8.4 Hz, 2H), 3.83-3.68 (m, 3H), 3.43-3.19 (m, 2H), 2.99-2.87(m, 1H), 2.87-2.76 (m, 1H), 2.62 (t, J=11.5 Hz, 1H), 2.49-2.39 (m, 1H),2.27 (s, 3H), 2.25-2.12 (m, 2H), 1.96-1.85 (m, 2H). Data for P-3: 2.0mg; LCMS (method U) RT 2.20 min (76% AP), m/z 405.2, 427.2 (M+H⁺,M+Na⁺); chiral HPLC (method A-3) RT 11.46 min, 76.3% AP; ¹H NMR (500MHz, chloroform-d) δ 7.50 (dd, J=11.7, 2.1 Hz, 1H), 7.26 (dd, J=8.5, 2.4Hz, 1H), 7.24-7.16 (m, 3H), 6.83 (d, J=8.5 Hz, 2H), 3.83-3.71 (m, 3H),3.36 (br. s., 1H), 3.31-3.22 (m, 1H), 3.15 (br. s., 1H), 3.00-2.88 (m,1H), 2.82 (dd, 1H), 2.50-2.42 (m, 1H), 2.28 (s, 3H), 2.25-2.12 (m, 3H),1.95-1.86 (m, 1H). Data for P-4: 7.1 mg; LCMS (method U) RT 2.19 min(84% AP), m/z 405.2, 427.2 (M+H⁺, M+Na⁺); chiral HPLC (method A-3) RT12.58 min, 89.5% AP; ¹H NMR (500 MHz, chloroform-d) δ 7.49 (dd, J=11.9,1.8 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.24-7.14 (m, 3H), 6.83 (d, J=8.4Hz, 2H), 3.83-3.70 (m, 3H), 3.43-3.19 (m, 3H), 2.99-2.87 (m, 1H), 2.63(t, J=11.4 Hz, 1H), 2.49-2.39 (m, 1H), 2.27 (s, 3H), 2.25-2.12 (m, 3H),1.95-1.86 (m, 1H).

Example 56 Example 56 (Peak-1, Peak-2, Peak-3, and Peak-4)(S)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one,(S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one,(R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one,and(R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one

Step A. (R)-4-(4-(Benzyloxy)phenyl)-3,3-difluoropiperidine and(S)-4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine

Racemic 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine (Example 52, stepC, 5 g) was separated using chiral HPLC (method H-3) to yield both pureenantiomers E-1 (1.5 g, 4.94 mmol, 39.5% yield) and E-2 (1.4 g, 4.62mmol, 36.8% yield). The absolute configurations were not assigned. Datafor E-1: Chiral SFC (method C-6) RT 3.58 min, 100% AP; LCMS (method F)RT 2.32 min, 100% AP, m/z 304.0 (M+H⁺); HPLC (method H) RT 6.746 min,91.2% AP; ¹H NMR (400 MHz, DMSO-d₆) d ppm 1.72 (d, J=13.55 Hz, 1H) 1.94(dd, J=12.55, 4.02 Hz, 1H) 2.60 (t, J=12.05 Hz, 1H) 2.74-2.88 (m, 1H)2.98 (d, J=12.55 Hz, 1H) 3.04-3.20 (m, 2H) 5.10 (s, 2H) 6.95-7.02 (m,2H) 7.21 (d, J=8.53 Hz, 2H) 7.30-7.50 (m, 5H).

Data for E-2: Chiral SFC (method C-6) RT 6.56 min, 99.3% AP; LCMS(method F) RT 2.32 min, 97.5% AP, m/z 304.0 (M+H⁺); HPLC (method H) RT6.767 min, 91.7% AP. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72 (d, J=13.55Hz, 1H) 1.94 (dd, J=12.55, 4.02 Hz, 1H) 2.60 (t, J=12.05 Hz, 1H)2.74-2.88 (m, 1H) 2.98 (d, J=12.55 Hz, 1H) 3.04-3.20 (m, 2H) 5.10 (s,2H) 6.95-7.02 (m, 2H) 7.21 (d, J=8.53 Hz, 2H) 7.30-7.50 (m, 5H).

Step B. 4-(3,3-Difluoropiperidin-4-yl)phenol

To a stirred solution of 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine(0.6 g, 2 mmol) (E-2 from step A) in 20 mL methanol at rt was added 10%Pd/C (0.21 g) and the reaction mixture was allowed to stir under 8 kPaof hydrogen pressure for 4 h.

The catalyst was removed by filtration and the mixture was concentratedunder vacuum. The residue was triturated with ether and the solid wasisolated by filtration to yield 0.4 g of E-2a4-(3,3-difluoropiperidin-4-yl)phenol (homochiral), which was useddirectly in the next step. LCMS (method P) RT 0.53 min, m/z 214.4(M+H⁺).

Step C.3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one

A mixture of 3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one(from Example 50, step B) (0.145 g, 0.51 mmol),4-(3,3-difluoropiperidin-4-yl)phenol (0.06 g, 0.28 mmol, E-2a fromExample 56 step B) and 0.2 mL of triethylamine (1.4 mmol) was heated at120° C. for 1 h. The cooled reaction mixture was partitioned betweenwater and ethyl acetate. The organic phase was washed with water andbrine, and then it was dried over Na₂SO₄, filtered, and concentrated toafford3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-oneas a pair of diastereomers. These diastereomers were separated viapreparative HPLC (method B) to yield3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-onehomochiral Examples 56 P-1 (10.7 mg) and P-2 (5.5 mg). The relative andabsolute configurations of Examples 56 P-1 and P-2 were not determinedand are arbitrarily named P-1 and P-2 based on the order of elutionduring the HPLC purification. Data for P-1: pale yellow solid; LCMS(method O) RT 1.21 min (95.8% AP) m/z 419.0 (M+H⁺); ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.55 (m, 3H) 1.78-1.90 (m, 1H), 1.90-2.01 (M, 1H),2.1-2.2 (m, 1H), 2.21-2.35 (m, 1H), 2.49 (m, 1H), 2.80-2.99 (m, 1H),3.01-3.10 (m, 4H), 3.33-3.38 (m, 3H), 3.63 (t, 1H), 5.40 (m, 1H), 6.75(m, 2H), 7.09-7.15 (m, 4H), 7.38-7.41 (m, 2H); ¹⁹F NMR δ ppm −76.948,−102.623, −103.262, −115.103, −115.743, −117.043. Data for P-2: solid;LCMS (methods N, O) 99% AP; ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.59 (d,J=7.03 Hz, 3H) 1.79-1.90 (m, 1H) 2.01-2.23 (m, 3H) 2.62-2.72 (m, 1H)2.86-3.19 (m, 5H) 3.40-3.74 (m, 2H) 4.36-4.56 (m, 1H) 5.28-5.48 (m, 1H)6.76 (d, J=9.04 Hz, 2H) 7.08-7.19 (m, 4H) 7.30-7.42 (m, 2H); ¹⁹F NMR δppm −76.938, −102.480, −012.630, −103.120, −103.146, −103.269, −114.559,−115.124, −115.199, −115.763, −116.990, −117.049.

Step D. 4-(3,3-Difluoropiperidin-4-yl)phenol

To a stirred solution of 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine(0.6 g, 2 mmol, E-1 from step A) in MeOH (20 mL) at rt was added 10%Pd/C (0.21 g) and the reaction mixture was allowed to stir under 8 kPaof hydrogen pressure for 4 h. The catalyst was removed by filtrationthrough Celite and the filtrate was concentrated under vacuum to afford0.4 g of homochiral E-1a 4-(3,3-difluoropiperidin-4-yl)phenol. LCMS(method P) RT 0.55 min (74% AP), m/z 214.4 (M+H⁺).

Step E.3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one

To a mixture of 3-bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one(0.134 g, 0.47 mmol, from Example 50, step B) and4-(3,3-difluoropiperidin-4-yl)phenol (0.05 g, 0.23 mmol, E-1a fromExample 56, step D) was added triethylamine (0.16 mL, 1.2 mmol) and theresulting mixture was heated at 120° C. for 1 h. After cooling, thereaction was partitioned between ethyl acetate and water. The layerswere separated and the organic phase was washed with water and brine,then dried over Na₂SO₄, filtered, and concentrated under vacuum. Theresidue was purified via preparative HPLC (method B) to yield thehomochiral Examples 56 P-3 and P-43-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-onediastereomers. The relative and absolute configurations of Examples 56P-3 and P-4 were not determined and are arbitrarily named P-3 and P-4based on the order of elution during the HPLC purification. Data forP-3: 11.5 mg pale yellow solid, LCMS (method O) RT 1.23 min (99.8% AP),m/z 419.0 (M+H⁺); ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.55 (d, J=7.2,3H), 1.83 (m, 1H), 1.91-1.99 (m, 1H), 2.10-2.30 (m, 2H), 2.57-2.64 (q,1H), 2.82-3.95 (m, 3H), 3.07-3.20, (m, 1H), 3.33-3.42 (m, 2H), 3.67 (t,J=9, 1H), 5.40 (d, J=7.2, 1H), 6.75 (m, 2H), 7.09-7.15 (m, 4H),7.37-7.41 (m, 2H); ¹⁹F NMR δ ppm −102.515, −103.158, −114.576, −115.216,−117.070. Data for P-4: 13.7 mg pale yellow solid; LCMS (method O) RT1.215 min (100% AP), m/z 419.0 (M+H⁺); ¹H NMR (400 MHz, methanol-d₄) δppm 1.59 (d, J=6.4, 3H), 1.80-1.90 (m, 1H), 2.01-2.29 (m, 3H), 2.53 (t,1H), 2.81-2.97 (m, 3H), 3.01-3.25 (m, 3H), 3.34-3.43 (m, 1H), 3.64 (t,J=8.8, 1H), 5.42 (d, J=7.2, 1H), 6.74-6.77 (m, 2H), 7.09-7.16 (m, 4H),7.35-7.38 (m, 2H); ¹⁹F NMR δ ppm −102.632, −103.271, −115.162, −115.801,−116.989.

General Procedure A: Used for Preparation of Examples 57-73

To a microwave vial containing 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol(25 mg, 0.128 mmol, E-1b from Example 50, step J) and the correspondinglactam bromide (0.256 mmol, compound LB) was added DMF (1 mL) andtriethylamine (0.09 mL, 0.64 mmol). The vial was capped and the reactionmixture was heated to 110° C. using microwave irradiation for 1 h. LC/MSdata were collected using method 100. The samples were directly purifiedby preparative HPLC under conditions B. Products were a mixture ofdiastereoisomers. In some cases, the diastereomers were furtherseparated into the individual homochiral components under the conditionsreported in the specific examples.

Example 57(S)-1-Benzyl-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

and Example 58(R)-1-Benzyl-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

A diastereomeric mixture of1-benzyl-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(prepared using general procedure A) was separated by SFC (method C-6)to afford the titled compounds of Examples 57 and 58. Data for Example57: SFC (Method 105) RT=3.06 min. LC/MS RT=2.01 min, (M+H)+=369.2; ¹HNMR (400 MHz, methanol-d4) δ ppm 1.78-1.88 (m, 2H) 2.04-2.12 (m, 1H)2.20 (ddd, J=16.56, 12.80, 3.26 Hz, 1H) 2.41-2.51 (m, 1H) 2.55-2.62 (m,1H) 2.67 (dt, J=9.79, 5.15 Hz, 2H) 3.01 (d, J=7.03 Hz, 1H) 3.12-3.18 (m,1H) 3.22-3.29 (m, 1H) 3.75 (t, J=8.53 Hz, 1H) 4.51-4.61 (m, 2H) 4.67(dt, J=10.04, 5.02 Hz, 1H) 6.70-6.83 (m, 2H) 7.07-7.14 (m, 2H) 7.27-7.33(m, 3H) 7.34-7.41 (m, 2H). Data for Example 58: SFC (Method 105) RT=5.76min. LC/MS RT=2.01 min, (M+H)+=369.2; ¹H NMR (400 MHz, methanol-d4) δppm 1.78-1.89 (m, 2H) 2.08 (dd, J=13.30, 8.78 Hz, 2H) 2.15-2.21 (m, 1H)2.43 (dt, J=10.29, 4.89 Hz, 2H) 2.51-2.60 (m, 2H) 2.63-2.71 (m, 2H) 2.77(br. s., 2H) 3.23-3.29 (m, 2H) 3.36-3.47 (m, 2H) 3.72 (t, J=8.78 Hz, 1H)4.40-4.48 (m, 2H) 4.54 (s, 1H) 6.71-6.80 (m, 2H) 7.07-7.14 (m, 2H)7.20-7.33 (m, 3H) 7.34-7.41 (m, 2H).

Example 593-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(2-methylbenzyl)pyrrolidin-2-one

A diastereomeric mixture of3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(2-methylbenzyl)pyrrolidin-2-one(Example 59) was prepared using general procedure A. Data for Example59: LC/MS RT=1.612 min, (M+H)+=383.0 ¹H NMR (400 MHz, DMSO-d₆) δ=9.20(s, 1H), 7.23-7.06 (m, 6H), 6.73-6.67 (m, 2H), 4.66-4.42 (m, 2H),4.33-4.26 (m, 1H), 3.64-3.55 (m, 1H), 3.43-3.36 (m, 1H), 3.19-3.04 (m,3H), 2.77-2.65 (m, 2H), 2.57-2.53 (m, 1H), 2.36-2.23 (m, 4H), 2.15-2.05(m, 1H), 1.98-1.86 (m, 1H), 1.77-1.56 (m, 1H).

Example 603-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-methylbenzyl)pyrrolidin-2-one

A diastereomeric mixture of3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-methylbenzyl)pyrrolidin-2-onewas prepared using general procedure A. Data for Example 60: LC/MSRT=1.628 min, (M+H)+=383.0 ¹H NMR (400 MHz, DMSO-d₆) δ=9.20 (s, 1H),7.27-7.20 (m, 1H), 7.09 (d, J=8.5 Hz, 3H), 7.05-6.98 (m, 2H), 6.73-6.67(m, 2H), 4.66-4.42 (m, 1H), 4.41-4.26 (m, 2H), 3.61-3.53 (m, 1H),3.44-3.34 (m, 1H), 3.21-3.08 (m, 3H), 2.95 (d, J=11.1 Hz, 1H), 2.76-2.65(m, 2H), 2.57-2.53 (m, 1H), 2.35-2.24 (m, 5H), 2.16-2.05 (m, 1H),1.98-1.86 (m, 1H), 1.78-1.55 (m, 2H).

Example 611-(4-(Difluoromethoxy)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

A diastereomeric mixture of1-(4-(difluoromethoxy)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-onewas prepared using general procedure A. Data for Example 61: LC/MSRT=1.594 min, (M+H)+=435.0 ¹H NMR (400 MHz, DMSO-d₆) δ=9.20 (s, 1H),7.41-7.01 (m, 7H), 6.73-6.67 (m, 2H), 4.66-4.44 (m, 1H), 4.44-4.30 (m,2H), 3.61-3.53 (m, 1H), 3.43-3.35 (m, 1H), 3.23-3.09 (m, 3H), 2.95 (d,J=10.0 Hz, 0H), 2.76-2.63 (m, 2H), 2.56 (d, J=4.6 Hz, 0H), 2.35-2.24 (m,1H), 2.15-2.05 (m, 1H), 1.98-1.86 (m, 1H), 1.78-1.56 (m, 2H).

Example 62(S)-1-(3-Chloro-4-(difluoromethoxy)phenyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one

and Example 63(R)-1-(3-Chloro-4-(difluoromethoxy)phenyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one

A diastereomeric mixture of1-(3-chloro-4-(difluoromethoxy)phenyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(prepared using general procedure A) was separated by SFC (method 101)to afford the titled compounds of Examples 62 and 63. Data for Example62: SFC (Method 106) RT=3.78 min.

LC/MS (Method O): RT=2.177 min, (M+H)+=455.0; ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.28-1.35 (m, 3H) 1.83-1.91 (m, 2H) 2.19-2.28 (m, 1H)2.32-2.43 (m, 2H) 2.49-2.63 (m, 2H) 2.73 (td, J=10.04, 4.52 Hz, 1H)2.98-3.12 (m, 2H) 3.20-3.29 (m, 1H) 3.76-3.91 (m, 3H) 4.69 (dt, J=10.04,5.02 Hz, 1H) 6.64-6.90 (m, 3H) 7.10-7.19 (m, 2H) 7.35 (d, J=9.04 Hz, 1H)7.62 (dd, J=9.04, 3.01 Hz, 1H) 8.01 (d, J=2.51 Hz, 1H). Data for Example63: SFC (Method 106) RT=5.03 min. LC/MS (Method O): RT=2.189 min,(M+H)+=455.0; ¹H NMR (400 MHz, methanol-d4) δ ppm 1.25 (t, J=7.28 Hz,3H) 1.80-1.90 (m, 2H) 2.22-2.39 (m, 3H) 2.45-2.63 (m, 3H) 2.81-2.95 (m,4H) 3.44-3.54 (m, 2H) 3.78-3.92 (m, 3H) 4.69-4.77 (m, 2H) 6.76 (d,J=9.04 Hz, 3H) 7.13 (d, J=8.53 Hz, 2H) 7.30-7.38 (m, 1H) 7.56-7.65 (m,1H) 8.01 (d, J=2.51 Hz, 1H).

Example 64(S)-1-(4-Chlorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

and Example 65(R)-1-(4-Chlorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

A diastereomeric mixture of1-(4-Chlorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(prepared using general procedure A) was separated by SFC (method 104)to afford the titled compounds of Example 64 and 65. Data for Example64: SFC (Method 106) RT=4.24 min. LC/MS (Method O): RT=2.10 min,(M+H)+=403.2; ¹H NMR (400 MHz, methanol-d₄) δ=7.42-7.35 (m, 2H),7.32-7.25 (m, 2H), 7.15-7.08 (m, 2H), 6.79-6.72 (m, 2H), 4.59-4.38 (m,3H), 3.74 (t, J=8.8 Hz, 1H), 3.30-3.23 (m, 2H), 3.18-3.10 (m, 1H), 3.02(d, J=11.0 Hz, 1H), 2.67 (dt, J=4.8, 9.9 Hz, 1H), 2.57 (dd, J=6.5, 10.5Hz, 1H), 2.49-2.41 (m, 1H), 2.26-2.03 (m, 2H), 1.88-1.80 (m, 2H). Datafor Example 65: SFC (Method 106) RT=7.88 min. LC/MS (Method O): RT=2.10min, (M+H)+=403.2; ¹H NMR (400 MHz, methanol-d4) δ=7.41-7.35 (m, 2H),7.32-7.25 (m, 2H), 7.14-7.08 (m, 2H), 6.79-6.73 (m, 2H), 4.58-4.40 (m,3H), 3.72 (t, J=8.8 Hz, 1H), 3.46-3.40 (m, 1H), 3.30-3.24 (m, 2H),2.80-2.75 (m, 1H), 2.74-2.52 (m, 2H), 2.44 (dt, J=4.5, 10.0 Hz, 1H),2.27-2.05 (m, 2H), 1.88-1.77 (m, 2H).

Example 66(S)-1-(4-Chloro-3-fluorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

and Example 67(R)-1-(4-Chloro-3-fluorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

A diastereomeric mixture of1-(4-chloro-3-fluorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(prepared using general procedure A) was separated by SFC (method 105)to afford the titled compounds of Example 66 and 67. Data for Example66: SFC (Method 105) RT=6.59 min. LC/MS (Method O): RT=2.122 min,(M+H)+=421.2; ¹H NMR (400 MHz, methanol-d4) δ ppm 1.77-1.88 (m, 2H)2.04-2.16 (m, 1H) 2.18-2.26 (m, 1H) 2.49-2.61 (m, 2H) 2.67-2.79 (m, 2H)3.43-3.52 (m, 2H) 3.60-3.64 (m, 1H) 3.70-3.75 (m, 1H) 4.43-4.53 (m, 2H)4.57-4.60 (m, 2H) 6.74-6.80 (m, 2H) 7.03-7.15 (m, 3H) 7.17-7.24 (m, 1H)7.45-7.52 (m, 1H). Data for Example 67: SFC (Method 105) RT=3.51 min.LC/MS (Method O): RT=2.124 min, (M+H)+=421.2; ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.84 (d, J=4.02 Hz, 2H) 2.10 (dd, J=13.05, 8.53 Hz,1H) 2.22 (dd, J=12.55, 3.51 Hz, 1H) 2.42-2.50 (m, 1H) 2.68 (td, J=9.79,4.52 Hz, 1H) 3.04 (d, J=13.05 Hz, 1H) 3.13-3.19 (m, 1H) 3.38 (br. s.,1H) 3.75 (t, J=8.53 Hz, 1H) 4.45-4.53 (m, 2H) 4.58 (s, 1H) 6.74-6.81 (m,2H) 7.12 (d, J=8.53 Hz, 3H) 7.20 (dd, J=10.04, 2.01 Hz, 1H) 7.44-7.53(m, 1H).

Example 683-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(1-phenylethyl)pyrrolidin-2-one

The titled compound of Example 68 was prepared using the generalprocedure A. Only one diastereomer was isolated after purification. Datafor Example 68: LC/MS RT=1.60 min, (M+H)+=383.0; ¹H NMR (400 MHz,DMSO-d₆) δ=9.20 (s, 1H), 7.39-7.33 (m, 2H), 7.31-7.25 (m, 3H), 7.09 (d,J=8.5 Hz, 2H), 6.72-6.68 (m, 2H), 5.29 (q, J=7.4 Hz, 1H), 4.66-4.46 (m,1H), 3.50 (t, J=8.5 Hz, 1H), 3.44-3.35 (m, 2H), 2.84-2.62 (m, 3H),2.35-2.23 (m, 1H), 2.06 (dd, J=4.3, 8.3 Hz, 1H), 1.91 (dd, J=8.3, 12.3Hz, 1H), 1.76-1.68 (m, 1H), 1.59 (dd, J=4.3, 12.8 Hz, 1H), 1.48 (d,J=7.0 Hz, 2H).

Example 691-(3,4-Difluorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

The titled compound of example 69 was prepared as a mixture ofdiastereomers using general procedure A. Data for Example 69: LC/MSRT=1.568 min, (M+H)+=405.0; ¹H NMR (400 MHz, DMSO-d₆) δ=9.20 (s, 1H),7.47-7.38 (m, 1H), 7.32-7.25 (m, 1H), 7.09 (d, J=8.0 Hz, 3H), 6.73-6.68(m, 2H), 4.66-4.41 (m, 1H), 4.37 (d, J=4.0 Hz, 2H), 3.63-3.54 (m, 1H),3.44-3.35 (m, 1H), 3.16 (s, 3H), 2.99-2.92 (m, 1H), 2.76-2.65 (m, 2H),2.57-2.54 (m, 1H), 2.35-2.23 (m, 1H), 2.08 (s, 1H), 2.00-1.88 (m, 1H),1.80-1.54 (m, 2H).

Example 701-(3,4-Dichlorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

The titled compound of example 70 was prepared as a mixture ofdiastereomers using the general procedure A. Data for Example 70: ¹H NMR(400 MHz, DMSO-d₆) δ=9.20 (s, 1H), 7.63 (dd, J=0.8, 8.4, 1H), 7.50 (s,1H), 7.22 (dd, J=1.2, 8, 1H), 7.08 (d, J=8.4, 2H), 6.90 (dd, J=2, 6.4,2H), 4.60 (m, 1H), 4.45 (m, 1H), 4.39 (m, 1H), 3.58 (m, 1H), 3.40 (m,1H), 3.30-3.10 (m, 3H), 2.69 (m, 2H), 2.35-2.21 (m, 1H), 2.10 (m, 1H),1.95 (m, 1H), 1.70 (m, 1H), 1.60 (m, 1H).

Example 71(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)-benzyl)pyrrolidin-2-one

and Example 72(R)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)benzyl)-pyrrolidin-2-one

A diastereomeric mixture of3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)benzyl)-pyrrolidin-2-one(prepared using general procedure A) was separated by SFC (method 105)to afford the titled compounds of Example 71 and 72. Data for Example71: SFC (Method 105) RT=2.31 min. LC/MS (Method 0): RT=2.233 min,(M+H)+=437.2; ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.68 (d, J=8.16 Hz,2H) 7.48 (d, J=8.03 Hz, 2H) 7.08-7.15 (m, 2H) 6.70-6.78 (m, 2H)4.50-4.70 (m, 3H) 3.76 (t, J=8.88 Hz, 1H) 3.12-3.18 (m, 1H) 2.99-3.07(m, 1H) 2.68 (td, J=9.91, 4.77 Hz, 1H) 2.53-2.62 (m, 1H) 2.42-2.50 (m,1H) 2.17-2.27 (m, 1H) 2.04-2.16 (m, 1H) 1.80-1.88 (m, 1H). Data forExample 72: SFC (Method 105) RT=3.31 min. LC/MS (Method O): RT=2.208min, (M+H)+=437.2; ¹H NMR (400 MHz, methanol-d4) δ ppm 7.68 (d, J=8.09Hz, 3H) 7.48 (d, J=8.03 Hz, 3H) 7.09-7.14 (m, 4H) 6.71-6.79 (m, 2H)4.51-4.71 (m, 3H) 3.74 (t, J=8.97 Hz, 1H) 3.41-3.47 (m, 1H) 2.74-2.83(m, 0H) 2.65-2.73 (m, 1H) 2.51-2.62 (m, 1H) 2.44 (td, J=9.99, 4.80 Hz,1H) 2.17-2.27 (m, 1H) 2.05-2.16 (m, 1H) 1.76-1.87 (m, 2H).

Example 731-(3-Chloro-4-fluorobenzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

The titled compound of example 73 was prepared as a mixture ofdiastereomers using general procedure A. Data for Example 73: LC/MSRT=1.674 min, (M+H)+=421.0; ¹H NMR (400 MHz, DMSO-d₆) δ=9.20 (s, 1H),7.48-7.36 (m, 2H), 7.29-7.21 (m, 1H), 7.09 (d, J=8.5 Hz, 2H), 6.73-6.67(m, 2H), 4.38 (d, J=4.0 Hz, 3H), 3.64-3.53 (m, 1H), 3.44-3.35 (m, 1H),3.16 (s, 3H), 2.99-2.91 (m, 1H), 2.76-2.63 (m, 2H), 2.36-2.22 (m, 1H),2.08 (s, 1H), 2.00-1.85 (m, 1H), 1.79-1.52 (m, 2H).

General Procedure B: Used for Preparation of Examples 74-89

To a microwave vial containing 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol(23 mg, 0.12 mmol, E-2b from Example 50, Step G) and the correspondinglactam bromide (0.21 mmol, compound LB) was added DMF (1 mL) andtriethylamine (0.08 mL, 0.59 mmol). The vial was capped and the reactionmixture was heated to 110° C. using microwave irradiation for 1 h. LC/MSdata were collected using method 100. The samples were directly purifiedby preparative HPLC under conditions B. Products are a mixture ofdiastereoisomers. In some cases, the diastereo-isomers were furtherseparated into the individual homochiral components under the conditionsreported in the specific examples.

Example 74(S)-1-Benzyl-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

and Example 75(R)-1-Benzyl-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one

A diastereomeric mixture of1-benzyl-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(prepared using general procedure B) was separated by SFC (method 105)to afford the titled compounds of Example 74 and 75. Data for Example74: SFC (Method 105) RT=3.59 min. LC/MS (Method O): RT=2.099 min,(M+H)+=369.2; ¹H NMR (400 MHz, methanol-d4) δ ppm 7.26-7.40 (m, 5H)7.08-7.13 (m, 2H) 6.71-6.79 (m, 2H) 4.40-4.71 (m, 3H) 3.68-3.75 (m, 1H)3.38-3.45 (m, 1H) 3.22-3.31 (m, 2H) 2.74-2.81 (m, 1H) 2.64-2.72 (m, 1H)2.51-2.63 (m, 1H) 2.43 (td, J=10.01, 4.83 Hz, 1H) 2.14-2.24 (m, 1H)2.02-2.13 (m, 1H) 1.75-1.87 (m, 2H). Data for Example 75: SFC (Method105) RT=6.2 min. LC/MS (Method O): RT=2.091 min, (M+H)+=369.2; ¹H NMR(400 MHz, methanol-d4) δ ppm 7.25-7.39 (m, 5H) 7.03-7.14 (m, 2H)6.70-6.84 (m, 2H) 4.38-4.72 (m, 3H) 3.74 (t, J=8.82 Hz, 1H) 3.22-3.30(m, 2H) 3.10-3.18 (m, 1H) 2.94-3.05 (m, 2H) 2.66 (td, J=9.91, 4.77 Hz,1H) 2.51-2.60 (m, 1H) 2.40-2.49 (m, 1H) 2.14-2.25 (m, 1H) 1.99-2.12 (m,1H) 1.79-1.89 (m, 2H).

Example 763-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(2-methylbenzyl)pyrrolidin-2-one

The titled compound of example 76 was prepared as a mixture ofdiastereomers using the general procedure B. Data for Example 76: LC/MSRT=1.588 min, (M+H)+=383.0; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56-1.78(m, 2H) 1.87-1.97 (m, 1H) 2.08 (s, 1H) 2.23-2.35 (m, 5H) 2.64-2.79 (m,2H) 3.04-3.18 (m, 3H) 3.36-3.44 (m, 1H) 3.60 (d, J=7.03 Hz, 1H)4.27-4.34 (m, 1H) 4.43-4.65 (m, 2H) 6.66-6.73 (m, 2H) 7.06-7.22 (m, 6H)9.20 (s, 1H).

Example 773-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-methylbenzyl)pyrrolidin-2-one

The titled compound of example 77 was prepared as a mixture ofdiastereomers using the general procedure B. Data for Example 77: LC/MSRT=1.600 min, (M+H)+=383.0; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57-1.76(m, 2H) 1.86-1.98 (m, 1H) 2.08 (s, 1H) 2.29 (s, 2H) 2.65-2.76 (m, 1H)3.09-3.21 (m, 2H) 3.57 (d, J=7.53 Hz, 1H) 4.25-4.41 (m, 2H) 4.44-4.69(m, 1H) 6.66-6.74 (m, 2H) 6.98-7.04 (m, 2H) 7.09 (d, J=8.53 Hz, 3H)7.20-7.28 (m, 1H) 9.21 (s, 1H).

Example 781-(4-(Difluoromethoxy)benzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

The titled compound of example 78 was prepared as a mixture ofdiastereomers using the general procedure B. Data for Example 78: LC/MSRT=1.565 min, (M+H)+=435.0; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.53-1.75(m, 2H) 1.86-1.97 (m, 1H) 2.04-2.14 (m, 1H) 2.20-2.35 (m, 1H) 2.63-2.78(m, 1H) 3.06-3.24 (m, 2H) 3.51-3.61 (m, 1H) 4.37 (d, J=12.55 Hz, 2H)4.46-4.66 (m, 1H) 6.70 (d, J=8.53 Hz, 1H) 6.99-7.11 (m, 1H) 7.13-7.23(m, 1H) 7.26-7.32 (m, 1H) 7.40 (s, 1H) 9.21 (s, 1H).

Example 791-(3-Chloro-4-(difluoromethoxy)phenyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one

The titled compound of example 79 was prepared as a mixture ofdiastereomers using the general procedure B. Data for Example 79: LC/MSRT=1.762 min, (M+H)+=455.0; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59-1.80(m, 2H) 2.01-2.14 (m, 1H) 2.20-2.27 (m, 1H) 2.30-2.41 (m, 1H) 2.72-2.80(m, 1H) 3.17 (s, 1H) 3.69-3.84 (m, 3H) 4.41-4.69 (m, 1H) 6.62-6.75 (m,2H) 6.98-7.27 (m, 4H) 7.35-7.45 (m, 2H) 7.64 (d, J=3.51 Hz, 1H) 8.03 (t,J=2.51 Hz, 1H) 9.13-9.30 (m, 1H).

Example 80(S)-1-(4-Chlorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

and Example 81(R)-1-(4-Chlorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

A diastereomeric mixture of1-(4-chlorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(prepared using general procedure B) was separated by SFC (method 105)to afford the titled compounds of Example 80 and 81. Data for Example80: SFC (Method 105) RT=4.58 min. LC/MS (Method 0): RT=2.216 min,(M+H)+=403.2; ¹H NMR (400 MHz, methanol-d4) δ ppm 1.76-1.89 (m, 2H)2.06-2.27 (m, 3H) 2.40-2.55 (m, 2H) 2.65-2.70 (m, 1H) 2.77 (d, J=10.54Hz, 1H) 3.39-3.46 (m, 2H) 3.62 (s, 1H) 3.72 (t, J=8.78 Hz, 2H) 4.36-4.60(m, 4H) 6.74-6.78 (m, 2H) 7.11 (d, J=8.53 Hz, 2H) 7.24-7.30 (m, 2H)7.35-7.41 (m, 2H). Data for Example 81: SFC (Method 105) RT=9.5 min.LC/MS (Method O): RT=2.233 min, (M+H)+=403.2; ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.84 (d, J=3.51 Hz, 2H) 2.45 (dd, J=14.81, 11.29 Hz,1H) 2.68 (dd, J=10.04, 4.52 Hz, 1H) 2.97-3.06 (m, 2H) 3.10-3.16 (m, 2H)3.25-3.31 (m, 2H) 3.62 (s, 1H) 4.49 (d, J=19.58 Hz, 3H) 4.66 (dd,J=10.04, 5.02 Hz, 2H) 6.72-6.79 (m, 2H) 7.12 (d, J=8.53 Hz, 2H)7.26-7.32 (m, 2H) 7.35-7.40 (m, 2H).

Example 82(S)-1-(4-Chloro-3-fluorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

and Example 83(R)-1-(4-Chloro-3-fluorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

A diastereomeric mixture of1-(4-chloro-3-fluorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(prepared using general procedure B) was separated by SFC (method 106)to afford the titled compounds of Example 82 and 83. Data for Example82: SFC (Method 106) RT=3.9 min. LC/MS (Method O): RT=2.081 min,(M+H)+=421.2; ¹H NMR (400 MHz, methanol-d4) δ ppm 7.44-7.50 (m, 1H)7.16-7.21 (m, 1H) 7.08-7.14 (m, 1H) 6.72-6.81 (m, 2H) 4.42-4.71 (m, 4H)3.69-3.75 (m, 1H) 3.40-3.47 (m, 1H) 3.25-3.31 (m, 1H) 2.74-2.80 (m, 1H)2.64-2.72 (m, 1H) 2.53-2.62 (m, 1H) 2.39-2.48 (m, 1H) 2.17-2.27 (m, 1H)2.04-2.16 (m, 1H) 1.77-1.87 (m, 2H). Data for Example 83: SFC (Method106) RT=7.05 min. LC/MS (Method O): RT=2.210 min, (M+H)+=421.2; ¹H NMR(400 MHz, methanol-d4) δ ppm 7.45-7.50 (m, 1H) 7.17-7.22 (m, 1H)7.08-7.14 (m, 2H) 6.73-6.78 (m, 2H) 4.43-4.70 (m, 3H) 3.71-3.78 (m, 1H)3.25-3.31 (m, 1H) 3.10-3.18 (m, 1H) 2.98-3.08 (m, 1H) 2.62-2.71 (m, 1H)2.52-2.61 (m, 1H) 2.39-2.49 (m, 1H) 2.17-2.27 (m, 1H) 2.03-2.15 (m, 1H)1.79-1.90 (m, 2H).

Example 843-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-phenylethyl)pyrrolidin-2-one

The titled compound of example 84 was prepared as a mixture ofdiastereomers using the general procedure B. Data for Example 84: LC/MSRT=1.574 min, (M+H)+=383.0; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.48 (d,J=7.53 Hz, 3H) 1.84-1.94 (m, 1H) 2.00-2.13 (m, 1H) 2.23-2.31 (m, 1H)2.66-2.75 (m, 1H) 2.81 (dt, J=9.66, 7.72 Hz, 1H) 2.95 (d, J=9.04 Hz, 1H)3.12-3.19 (m, 1H) 3.51 (t, J=8.53 Hz, 1H) 4.42-4.62 (m, 1H) 5.26-5.32(m, 1H) 6.67-6.74 (m, 2H) 7.07-7.11 (m, 2H) 7.25-7.31 (m, 3H) 7.33-7.39(m, 2H) 9.20 (s, 1H).

Example 851-(3,4-Difluorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one

The titled compound of example 85 was prepared as a mixture ofdiastereomers using the general procedure B. Data for Example 85: LC/MSRT=1.540 min, (M+H)+=405.0 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51-1.78 (m,2H) 1.86-2.01 (m, 1H) 2.08 (s, 1H) 2.22-2.35 (m, 1H) 2.71 (br. s., 2H)3.09-3.24 (m, 3H) 3.54-3.64 (m, 1H) 4.37 (d, J=4.02 Hz, 2H) 4.43-4.69(m, 1H) 6.70 (d, J=8.53 Hz, 2H) 7.09 (d, J=8.53 Hz, 3H) 7.24-7.32 (m,1H) 7.43 (s, 1H) 9.20 (s, 1H).

Example 861-(3,4-Dichlorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one

The titled compound of example 86 was prepared as a mixture ofdiastereomers using the general procedure B. Data for Example 86: LC/MSRT=1.768 min, (M+H)+=437.0 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51-1.76 (m,2H) 1.85-2.00 (m, 1H) 2.05-2.15 (m, 1H) 2.21-2.34 (m, 1H) 2.66-2.75 (m,2H) 3.07-3.25 (m, 3H) 3.37 (s, 1H) 3.59 (d, J=6.53 Hz, 1H) 4.39 (d,J=5.52 Hz, 2H) 4.43 (s, 1H) 6.67-6.74 (m, 2H) 7.09 (d, J=8.53 Hz, 2H)7.20-7.28 (m, 1H) 7.50 (t, J=2.01 Hz, 1H) 7.62 (dd, J=8.03, 1.00 Hz, 1H)9.21 (s, 1H).

Example 87(S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)benzyl)-pyrrolidin-2-one

and Example 88(R)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)benzyl)-pyrrolidin-2-one

A diastereomeric mixture of3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)benzyl)-pyrrolidin-2-one(prepared using general procedure B) was separated by SFC (method 106)to afford the titled compounds of Example 87 and 88. Data for Example87: SFC (Method 106) RT=2.09 min. LC/MS (Method O): RT=2.14 min,(M+H)+=437.2; ¹H NMR (400 MHz, methanol-d₄) δ=7.69 (d, J=8.0 Hz, 2H),7.49 (d, J=8.0 Hz, 2H), 7.15-7.09 (m, 2H), 6.80-6.72 (m, 2H), 4.71-4.51(m, 3H), 3.74 (t, J=9.0 Hz, 1H), 3.48-3.41 (m, 1H), 3.30-3.25 (m, 2H),2.83-2.75 (m, 1H), 2.73-2.65 (m, 1H), 2.62-2.52 (m, 1H), 2.45 (dt,J=4.5, 10.0 Hz, 1H), 2.28-2.07 (m, 2H), 1.88-1.77 (m, 2H). Data forExample 88: SFC (Method 106) RT=3.19 min. LC/MS (Method O): RT=2.13 min,(M+H)+=437.2; ¹H NMR (400 MHz, methanol-d4) δ=7.72-7.66 (m, 2H),7.53-7.45 (m, 2H), 7.16-7.08 (m, 2H), 6.80-6.72 (m, 2H), 4.69-4.49 (m,3H), 3.81-3.72 (m, 1H), 3.32-3.26 (m, 2H), 3.19-3.11 (m, 1H), 3.09-3.00(m, 1H), 2.74-2.65 (m, 1H), 2.62-2.53 (m, 1H), 2.51-2.42 (m, 1H),2.28-2.18 (m, 1H), 2.16-2.04 (m, 1H), 1.90-1.79 (m, 2H).

Example 891-(3-Chloro-4-fluorobenzyl)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

The titled compound of example 89 was prepared as a mixture ofdiastereomers using the general procedure B. Data for Example 89: LC/MSRT=1.645 min, (M+H)+=421.0 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.49-1.79 (m,2H) 1.86-1.99 (m, 2H) 2.08 (s, 2H) 2.21-2.35 (m, 2H) 2.65-2.76 (m, 2H)3.16 (s, 4H) 3.36-3.44 (m, 1H) 3.54-3.64 (m, 1H) 4.38 (d, J=4.02 Hz, 2H)4.44-4.68 (m, 1H) 6.70 (d, J=8.53 Hz, 2H) 7.09 (d, J=8.53 Hz, 2H)7.21-7.27 (m, 1H) 7.40 (s, 2H) 9.20 (s, 1H).

General Procedure C: Used for Preparation of Examples 90-117

To a microwave vial containing 4-(3,3-difluoropiperidin-4-yl)phenol HCl(30 mg, 0.14 mmol, E-1a from Example 56, Step D) and the appropriatelactam bromide (0.28 mmol, compound LB) was added DMF (1 mL) andtriethylamine (0.1 mL, 0.7 mmol). The vial was capped and the reactionmixture was heated to 120° C. using microwave irradiation for 1 h. LC/MSdata were collected using method 100. The samples were directly purifiedby preparative HPLC under conditions B. Products are a mixture ofdiastereoisomers. In some cases, the diastereo-isomers were furtherseparated into the individual homochiral components under the conditionsreported in the specific examples. Assignment of lactam stereochemistryfollowed biological activity but was not rigorously determinedchemically, therefore individual compounds are identified by theretention time in SFC. The absolute configuration of the homochiral4-(3,3-difluoropiperidin-4-yl)phenol used has not been determined.

Example 901-(3-Chloro-4-(difluoromethoxy)phenyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

The titled compound of example 90 was prepared as a mixture ofdiastereomers using the general procedure C. Data for Example 90: LC/MSRT=1.769 min, (M+H)+=473.0 ¹H NMR (400 MHz, DMSO-d₆) δ=9.31 (s, 1H),8.03 (t, J=3.0 Hz, 1H), 7.68-7.62 (m, 1H), 7.44-7.07 (m, 4H), 6.72 (d,J=8.0 Hz, 2H), 3.80 (d, J=10.0 Hz, 3H), 3.17 (d, J=5.0 Hz, 2H),3.06-2.85 (m, 2H), 2.73-2.60 (m, 1H), 2.48-2.43 (m, 1H), 2.35-2.22 (m,1H), 2.13-1.93 (m, 4H), 1.81-1.70 (m, 1H).

Example 91 (Peak-1)1-Benzyl-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

and Example 91 (Peak-2)1-Benzyl-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

1-Benzyl-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-onewas prepared as a mixture of diastereomers using the general procedureC. The mixture of diastereomers was separated into the individualhomochiral compounds of example 91 P-1 and P-2 by SFC using method 105.The relative and absolute configurations of were not determined and arearbitrarily named P-1 and P-2 based on the order of elution during theSFC purification. Data for Example 91, P-1: SFC (Method 105) RT=5.29min. LC/MS (Method O): RT=2.103 min, (M+H)+=387.2; ¹H NMR (400 MHz,methanol-d4) δ ppm 7.26-7.39 (m, 5H) 7.15 (d, J=8.35 Hz, 2H) 6.73-6.77(m, 2H) 4.41-4.59 (m, 3H) 3.69 (t, J=8.85 Hz, 1H) 3.36-3.42 (m, 1H)3.22-3.30 (m, 2H) 3.06 (d, J=7.28 Hz, 1H) 2.84-3.01 (m, 3H) 2.60-2.73(m, 1H) 1.98-2.28 (m, 3H) 1.82 (ddt, J=13.18, 4.76, 2.38, 2.38 Hz, 1H).Data for Example 91, P-2: SFC (Method 105) RT=5.18 min. LC/MS (MethodO): RT=2.117 min, (M+H)+=387.2; ¹H NMR (400 MHz, methanol-d4) δ ppm7.26-7.39 (m, 5H) 7.15 (d, J=8.41 Hz, 2H) 6.73-6.77 (m, 2H) 4.41-4.57(m, 2H) 3.72 (t, J=8.82 Hz, 1H) 3.22-3.30 (m, 1H) 3.03-3.18 (m, 4H)2.86-3.00 (m, 1H) 2.53 (t, J=11.39 Hz, 1H) 1.99-2.30 (m, 3H) 1.80-1.88(m, 1H).

Example 923-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(2-methylbenzyl)pyrrolidin-2-one

The titled compound of example 92 was prepared as a mixture ofdiastereomers using the general procedure C. Data for Example 92: LC/MSRT=1.609 min, (M+H)+=401.0 ¹H NMR (400 MHz, DMSO-d₆) δ=9.30 (d, J=1.5Hz, 1H), 7.22-7.07 (m, 6H), 6.71 (d, J=8.0 Hz, 2H), 4.48-4.42 (m, 1H),4.35-4.28 (m, 1H), 3.62 (d, J=9.0 Hz, 1H), 3.19-3.04 (m, 4H), 3.02-2.78(m, 2H), 2.69-2.54 (m, 1H), 2.45-2.32 (m, 1H), 2.25 (d, J=1.0 Hz, 3H),2.18-2.07 (m, 1H), 1.94 (d, J=17.1 Hz, 2H), 1.80-1.69 (m, 1H).

Example 933-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-methylbenzyl)pyrrolidin-2-one

The titled compound of example 93 was prepared as a mixture ofdiastereomers using the general procedure C. Data for Example 93: LC/MSRT=1.622 min, (M+H)+=401.0 ¹H NMR (400 MHz, DMSO-d₆) δ=9.30 (s, 1H),7.27-7.20 (m, 1H), 7.09 (d, J=8.0 Hz, 3H), 7.06-6.99 (m, 2H), 6.72 (d,J=8.0 Hz, 2H), 4.40-4.28 (m, 2H), 4.11-4.05 (m, 1H), 3.60 (d, J=8.5 Hz,1H), 3.39-3.34 (m, 1H), 3.23-2.77 (m, 6H), 2.69-2.54 (m, 1H), 2.45-2.32(m, 1H), 2.29 (s, 3H), 2.19-2.08 (m, 1H), 2.04-1.85 (m, 2H), 1.79-1.69(m, 1H).

Example 943-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(difluoromethoxy)benzyl)-pyrrolidin-2-one

The titled compound of example 94 was prepared as a mixture ofdiastereomers using the general procedure C. Data for Example 94: LC/MSRT=1.595 min, (M+H)+=453.0 ¹H NMR (400 MHz, DMSO-d₆) δ=9.30 (d, J=1.0Hz, 1H), 7.42-7.02 (m, 8H), 6.71 (d, J=8.0 Hz, 2H), 4.43-4.32 (m, 2H),3.60 (d, J=8.0 Hz, 1H), 3.40-3.33 (m, 1H), 3.24-3.04 (m, 3H), 3.02-2.76(m, 2H), 2.69-2.54 (m, 1H), 2.43-2.31 (m, 1H), 2.20-2.07 (m, 1H),2.03-1.85 (m, 1H), 1.79-1.69 (m, 1H).

Example 95 (Peak-1)(3S)-1-(4-Chlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

and Example 95 (Peak-2)(3R)-1-(4-Chlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

1-(4-Chlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-onewas prepared as a mixture of diastereomers using the general procedureC. The mixture of diastereomers was separated into the individualhomochiral compounds of example 95 P-1 and P-2 by SFC (method 105). Thestereochemical configurations were not determined and are arbitrarilynamed P-1 and P-2. Data for Example 95, P-1: SFC (Method 105) RT=5.29min. LC/MS (Method O): RT=2.062 min, (M+H)+=421.2; ¹H NMR (400 MHz,methanol-d₄) δ=7.41-7.35 (m, 2H), 7.32-7.26 (m, 2H), 7.15 (d, J=8.5 Hz,2H), 6.79-6.73 (m, 2H), 4.55-4.40 (m, 2H), 3.69 (t, J=8.8 Hz, 1H),3.43-3.37 (m, 1H), 3.31-3.24 (m, 2H), 3.01-2.84 (m, 3H), 2.73-2.58 (m,1H), 2.28-2.01 (m, 3H), 1.83 (ddd, J=2.0, 1H). Data for Example 95, P-2:SFC (Method 105) RT=8.79 min. LC/MS (Method O): RT=2.059 min,(M+H)+=421.2; ¹H NMR (400 MHz, methanol-d₄) δ=7.40-7.34 (m, 2H),7.32-7.26 (m, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.78-6.73 (m, 2H), 4.55-4.39(m, 2H), 3.72 (t, J=8.8 Hz, 1H), 3.62 (s, 1H), 3.30-3.24 (m, 2H),3.20-3.07 (m, 3H), 2.98-2.86 (m, 1H), 2.53 (s, 1H), 2.30-2.02 (m, 3H),1.86 (br. s., 1H).

Example 96 (Peak-1)(3S)-1-(4-Chloro-3-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

and Example 96 (Peak-2)(3R)-1-(4-Chloro-3-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

1-(4-Chloro-3-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-onewas prepared as a mixture of diastereomers using the general procedureC. The mixture of diastereomers was separated into the individualhomochiral compounds of example 96 P-1 and P-2 by SFC (method 105). Thestereochemical configurations were not determined and are arbitrarilynamed P-1 and P-2. Data for Example 96, P-1: SFC (Method 105) RT=5.13min. LC/MS (Method O): RT=2.214 min, (M+H)+=439.0; ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.47-1.51 (m, 1H) 1.84 (d, J=13.05 Hz, 1H) 2.05-2.31(m, 3H) 2.54-2.66 (m, 1H) 2.83-3.02 (m, 3H) 3.29-3.32 (m, 1H) 3.39-3.56(m, 2H) 3.65-3.74 (m, 1H) 4.41-4.55 (m, 2H) 6.71-6.78 (m, 2H) 7.07-7.35(m, 4H) 7.46-7.52 (m, 1H). Data for Example 96, P-2: SFC (Method 105)RT=7.15 min. LC/MS (Method O): RT=2.211 min, (M+H)+=439.0; ¹H NMR (400MHz, methanol-d4) δ ppm 1.81-1.92 (m, 1H) 2.01-2.30 (m, 3H) 2.46-2.58(m, 1H) 3.03-3.11 (m, 1H) 3.10-3.21 (m, 2H) 3.24-3.32 (m, 1H) 3.72 (t,J=8.78 Hz, 1H) 4.42-4.56 (m, 2H) 6.72-6.79 (m, 2H) 7.09-7.23 (m, 4H)7.43-7.51 (m, 1H).

Example 973-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3,4-difluorobenzyl)pyrrolidin-2-one

The titled compound of example 97 was prepared as a mixture ofdiastereomers using the general procedure C. Data for Example 97: LC/MSRT=1.569 min, (M+H)+=423.0; ¹H NMR (400 MHz, DMSO-d₆) δ=9.30 (d, J=1.0Hz, 1H), 7.46-7.37 (m, 1H), 7.33-7.25 (m, 1H), 7.09 (d, J=8.5 Hz, 3H),6.71 (d, J=8.5 Hz, 2H), 4.37 (s, 2H), 3.65-3.57 (m, 1H), 3.43-3.35 (m,1H), 3.27-3.04 (m, 4H), 3.03-2.76 (m, 2H), 2.63-2.58 (m, 1H), 2.44-2.32(m, 1H), 2.21-2.07 (m, 1H), 2.04-1.87 (m, 2H), 1.79-1.69 (m, 1H).

Example 981-(3,4-Dichlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

The titled compound of example 98 was prepared as a mixture ofdiastereomers using the general procedure C. Data for Example 98: LC/MSRT=1.843 min, (M+H)+=454.9; ¹H NMR (400 MHz, DMSO-d₆) δ=9.33-9.28 (m,1H), 7.62 (dd, J=1.3, 8.3 Hz, 1H), 7.50 (t, J=1.8 Hz, 1H), 7.24 (d,J=2.0 Hz, 1H), 7.09 (d, J=8.5 Hz, 2H), 6.71 (d, J=8.5 Hz, 2H), 4.39 (s,2H), 4.11-4.05 (m, 1H), 3.65-3.57 (m, 1H), 3.17 (d, J=5.0 Hz, 4H),3.03-2.76 (m, 2H), 2.42-2.31 (m, 1H), 2.21-2.07 (m, 1H), 1.90 (s, 2H),1.79-1.69 (m, 1H).

Example 99 (Peak-1)(3S)-3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)benzyl)-pyrrolidin-2-one

and Example 99 (Peak-2)(3S)-3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)benzyl)-pyrrolidin-2-one

3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)benzyl)-pyrrolidin-2-onewas prepared as a mixture of diastereomers using the general procedureC. The mixture of diastereomers was separated into the individualhomochiral compounds of example 99 P-1 and P-2 by SFC using method 100.The relative and absolute configurations of were not determined and arearbitrarily named P-1 and P-2 based on the order of elution during theSFC purification. Data for Example 99, P-1: SFC (Method 105) RT=2.8 min.LC/MS (Method O): RT=2.156 min, (M+H)+=455.2; ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.80-1.86 (m, 1H) 2.02-2.32 (m, 3H) 2.61-2.74 (m, 1H)2.84-3.06 (m, 3H) 3.23-3.30 (m, 1H) 3.38-3.46 (m, 1H) 3.71 (t, J=8.78Hz, 1H) 4.50-4.64 (m, 2H) 6.71-6.79 (m, 2H) 7.15 (d, J=8.53 Hz, 2H) 7.49(d, J=8.03 Hz, 2H) 7.68 (d, J=8.53 Hz, 2H). Data for Example 99, P-2:SFC (Method 105) RT=3.36 min. LC/MS (Method O): RT=2.152 min,(M+H)+=455.2; ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.27-1.37 (m, 1H)2.02-2.30 (m, 3H) 2.54 (t, J=11.04 Hz, 1H) 3.07-3.20 (m, 4H) 3.24-3.30(m, 2H) 3.35-3.56 (m, 1H) 3.74 (t, J=8.78 Hz, 1H) 4.55-4.60 (m, 2H)6.72-6.79 (m, 2H) 7.15 (d, J=8.53 Hz, 2H) 7.49 (d, J=8.03 Hz, 2H) 7.68(d, J=8.03 Hz, 2H).

Example 1001-(3-Chloro-4-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

The titled compound of example 100 was prepared as a mixture ofdiastereomers using the general procedure C. Data for Example 100: LC/MSRT=1.726 min, (M+H)+=439.0; ¹H NMR (400 MHz, methanol-d₄) δ=7.47-7.42(m, 1H), 7.30-7.23 (m, 2H), 7.18-7.12 (m, 2H), 6.79-6.72 (m, 2H),4.52-4.41 (m, 2H), 3.75-3.66 (m, 1H), 3.30-3.26 (m, 1H), 3.20-3.08 (m,2H), 3.01-2.83 (m, 2H), 2.71-2.49 (m, 1H), 2.33-2.07 (m, 3H), 1.89-1.79(m, 1H).

General Procedure D. Used for Preparation of Examples 101-139

To a microwave vial containing 4-(3,3-difluoropiperidin-4-yl)phenol (25mg, 0.12 mmol, E-2a, Example 56, step B) and the appropriate lactambromide (0.29 mmol, LB) was added DMF (1 mL) and triethylamine (0.08 mL,0.6 mmol). The vial was capped and the reaction mixture was heated to120° C. using microwave irradiation for 1 h. LC/MS data were collectedusing method 100. The samples were directly purified by preparative HPLCunder conditions B. Products are a mixture of diastereoisomers. In somecases, the diastereoisomers were further separated into the individualhomochiral components under the conditions reported in the specificexamples. Assignment of lactam stereochemistry could be inferred throughbiological activity, but was not unambiguously determined. Individualcompounds are identified by the retention time during SFC. The absoluteconfiguration of the homochiral 4-(3,3-difluoropiperidin-4-yl)phenolused has not been determined.

Example 101 (Peak-1)(3S)-1-(3-Chloro-4-(difluoromethoxy)phenyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one

and Example 101 (Peak-2)(3R)-1-(3-Chloro-4-(difluoromethoxy)phenyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one

1-(3-Chloro-4-(difluoromethoxy)phenyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-onewas prepared as a mixture of diastereomers using the general procedureD. The mixture of diastereomers was separated into the individualhomochiral compounds of example 101 P-1 and P-2 by SFC using method 106.The relative and absolute configurations of were not unambiguouslydetermined and are arbitrarily named P-1 and P-2 based on the order ofelution during the SFC purification. Data for Example 101, P-1: SFC(Method 106) RT=2.79 min; LC/MS (Method O): RT=2.208 min, (M+H)+=473.0;¹H NMR (400 MHz, methanol-d₄) δ ppm 1.89 (br. s., 1H) 2.15-2.25 (m, 2H)2.35-2.47 (m, 2H) 2.58-2.66 (m, 2H) 3.09-3.29 (m, 4H) 3.74-3.92 (m, 3H)6.65-7.04 (m, 3H) 7.16 (d, J=8.53 Hz, 1H) 7.34 (d, J=9.04 Hz, 1H)7.57-7.67 (m, 1H) 8.00 (d, J=2.51 Hz, 1H). Data for Example 101, P-2:SFC (Method 106) RT=3.36 min; LC/MS (Method O): RT=2.210 min,(M+H)+=473.0; ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.85 (d, J=13.05 Hz,1H) 2.12-2.27 (m, 2H) 2.34-2.44 (m, 1H) 2.68-2.82 (m, 2H) 2.87-3.10 (m,4H) 3.48-3.53 (m, 1H) 3.78-3.89 (m, 3H) 6.61-6.91 (m, 3H) 7.16 (d,J=8.53 Hz, 2H) 7.35 (d, J=9.04 Hz, 1H) 7.61 (dd, J=9.04, 2.51 Hz, 1H)8.00 (d, J=3.01 Hz, 1H).

Example 102 (Peak-1)(3S)-1-Benzyl-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

and Example 102 (Peak-2)(3R)-1-Benzyl-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

1-Benzyl-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-onewas prepared as a mixture of diastereomers using the general procedureD. The mixture of diastereomers was separated into the individualhomochiral compounds of example 102 P-1 and P-2 by SFC using method 105.The relative and absolute configurations of were not unambiguouslydetermined and are arbitrarily named P-1 and P-2 based on the order ofelution during the SFC purification. Data for Example 102, P-1: SFC(Method 105) RT=2.62 min; LC/MS (Method O): RT=2.106 min, (M+H)+=387.2;¹H NMR (400 MHz, methanol-d₄) δ=7.41-7.26 (m, 5H), 7.15 (d, J=8.5 Hz,2H), 6.79-6.72 (m, 2H), 4.58-4.41 (m, 2H), 3.72 (t, J=8.8 Hz, 1H),3.30-3.23 (m, 2H), 3.19-3.08 (m, 3H), 3.00-2.86 (m, 1H), 2.54 (t, J=11.5Hz, 1H), 2.30-2.01 (m, 3H), 1.85 (tdd, J=2.4, 4.6, 13.1 Hz, 1H). Datafor Example 102, P-2: LC/MS RT=1.633 min; (M+H)+=401.0 ¹H NMR (400 MHz,DMSO-d₆) δ=9.33-9.28 (m, 1H), 7.19 (d, J=1.5 Hz, 6H), 6.75-6.67 (m, 2H),4.50-4.41 (m, 1H), 4.35-4.25 (m, 1H), 3.69-3.53 (m, 1H), 3.22-3.02 (m,3H), 2.94-2.80 (m, 1H), 2.46-2.32 (m, 1H), 2.25 (s, 4H), 2.17-2.06 (m,1H), 1.99-1.65 (m, 3H).

Example 1033-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(2-methylbenzyl)pyrrolidin-2-one

The titled compound of example 100 was prepared as a mixture ofdiastereomers using the general procedure D. Data for Example 103: LC/MSRT=1.633 min; (M+H)+=401.0 ¹H NMR (400 MHz, DMSO-d₆) δ=9.33-9.28 (m,1H), 7.19 (d, J=1.5 Hz, 6H), 6.75-6.67 (m, 2H), 4.50-4.41 (m, 1H),4.35-4.25 (m, 1H), 3.69-3.53 (m, 1H), 3.22-3.02 (m, 3H), 2.94-2.80 (m,1H), 2.46-2.32 (m, 1H), 2.25 (s, 4H), 2.17-2.06 (m, 1H), 1.99-1.65 (m,3H).

Example 1043-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-methylbenzyl)pyrrolidin-2-one

The titled compound of example 104 was prepared as a mixture ofdiastereomers using the general procedure D. Data for Example 104: LC/MSRT=1.647 min; (M+H)+=401.0 ¹H NMR (400 MHz, DMSO-d₆) δ=9.31 (s, 1H),7.27-7.19 (m, 1H), 7.12-6.99 (m, 5H), 6.72 (d, J=8.0 Hz, 2H), 4.42-4.24(m, 2H), 3.60 (d, J=9.0 Hz, 1H), 3.22-3.03 (m, 3H), 2.92-2.56 (m, 2H),2.29 (s, 3H), 2.13 (br. s., 1H), 1.93 (br. s., 2H), 1.79-1.68 (m, 1H).

Example 1053-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(difluoromethoxy)benzyl)-pyrrolidin-2-one

The titled compound of example 105 was prepared as a mixture ofdiastereomers using the general procedure D. Data for Example 105: LC/MSRT=1.622 min; (M+H)+=453.0 ¹H NMR (400 MHz, DMSO-d₆) δ=9.31 (s, 1H),7.47-7.24 (m, 3H), 7.22-7.00 (m, 6H), 6.72 (d, J=8.5 Hz, 2H), 4.44-4.31(m, 2H), 3.60 (d, J=8.0 Hz, 1H), 3.23-3.05 (m, 4H), 3.00-2.77 (m, 2H),2.44-2.31 (m, 1H), 2.17-2.06 (m, 1H), 1.94 (d, J=17.1 Hz, 2H), 1.79-1.69(m, 1H).

Example 106 (Peak-1)(3S)-1-(4-Chlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

and Example 106 (Peak-2)(3R)-1-(4-Chlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

1-(4-Chlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-onewas prepared as a mixture of diastereomers using the general procedureD. The mixture of diastereomers was separated into the individualhomochiral compounds of example 106 P-1 and P-2 by SFC using method 106.The relative and absolute configurations were not determined and arearbitrarily named P-1 and P-2 based on the order of elution during theSFC purification. Data for Example 106, P-1: SFC (Method 106) RT=3.14min; LC/MS (Method O): RT=2.127 min, (M+H)+=421.2; ¹H NMR (400 MHz,methanol-d4) δ ppm 7.35-7.41 (m, 2H) 7.26-7.31 (m, 2H) 7.15 (d, J=8.35Hz, 2H) 6.73-6.78 (m, 2H) 4.40-4.54 (m, 2H) 3.69-3.75 (m, 1H) 3.61-3.62(m, 0H) 3.45-3.50 (m, 1H) 3.23-3.31 (m, 1H) 3.09-3.20 (m, 3H) 2.86-3.05(m, 1H) 2.49-2.58 (m, 1H) 2.00-2.31 (m, 3H) 1.79-1.90 (m, 1H). Data forExample 106, P-2: SFC (Method 106) RT=4.29 min; LC/MS (Method O):RT=2.128 min, (M+H)+=421.2; ¹H NMR (400 MHz, methanol-d4) δ ppm7.34-7.41 (m, 2H) 7.24-7.30 (m, 2H) 7.15 (d, J=8.35 Hz, 2H) 6.73-6.78(m, 2H) 4.48 (q, J=14.87 Hz, 2H) 3.69 (t, J=8.85 Hz, 1H) 3.62 (s, 1H)3.38-3.49 (m, 1H) 3.23-3.31 (m, 1H) 3.06 (q, J=7.26 Hz, 1H) 2.84-3.01(m, 2H) 2.60-2.73 (m, 1H) 1.98-2.31 (m, 3H) 1.79-1.89 (m, 1H).

Example 107 (Peak-1)(3S)-1-(4-Chloro-3-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

and Example 107 (Peak-2)(3R)-1-(4-Chloro-3-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

1-(4-Chloro-3-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-onewas prepared as a mixture of diastereomers using the general procedureD. The mixture of diastereomers was separated into the individualhomochiral compounds of example 107 P-1 and P-2 by SFC using method 105.The relative and absolute configurations were not determined and arearbitrarily named P-1 and P-2 based on the order of elution during theSFC purification. Data for Example 107, P-1: SFC (Method 105) RT=2.85min; LC/MS (Method O): RT=2.093 min, (M+H)+=439.0; ¹H NMR (400 MHz,methanol-d₄) δ ppm 1.85 (ddt, J=13.18, 4.64, 2.38, 2.38 Hz, 1H)2.03-2.31 (m, 3H) 2.53 (t, J=11.29 Hz, 1H) 3.05-3.12 (m, 1H) 3.13-3.18(m, 2H) 3.26-3.31 (m, 2H) 3.72 (t, J=8.78 Hz, 1H) 4.41-4.54 (m, 2H)6.73-6.79 (m, 2H) 7.08-7.23 (m, 4H) 7.48 (t, J=8.03 Hz, 1H). Data forExample 107, P-2: SFC (Method 105) RT=3.99 min; LC/MS (Method Q):RT=1.648 min, (M+H)+=439.0; ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.85(ddt, J=13.18, 4.64, 2.38, 2.38 Hz, 1H) 2.03-2.31 (m, 3H) 2.53 (t,J=11.29 Hz, 1H) 3.05-3.12 (m, 1H) 3.13-3.18 (m, 2H) 3.26-3.31 (m, 2H)3.72 (t, J=8.78 Hz, 1H) 4.41-4.54 (m, 2H) 6.73-6.79 (m, 2H) 7.08-7.23(m, 4H) 7.48 (t, J=8.03 Hz, 1H).

Example 108 (Peak-1)(3S)-3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3,4-difluorobenzyl)-pyrrolidin-2-one

and Example 108 (Peak-2)(3R)-3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3,4-difluorobenzyl)-pyrrolidin-2-one

3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3,4-difluorobenzyl)pyrrolidin-2-onewas prepared as a mixture of diastereomers using the general procedureD. The mixture of diastereomers was separated into the individualhomochiral compounds of example 108 P-1 and P-2 by SFC using method 105.The relative and absolute configurations were not determined and arearbitrarily named P-1 and P-2 based on the order of elution during theSFC purification. Data for Example 108, P-1: SFC (Method 105) RT=2.27min; LC/MS (Method O): RT=2.149 min, (M+H)+=423.2; ¹H NMR (400 MHz,methanol-d₄) δ=7.32-7.19 (m, 2H), 7.18-7.08 (m, 3H), 6.79-6.72 (m, 2H),4.60-4.40 (m, 2H), 3.72 (t, J=9.0 Hz, 1H), 3.30-3.24 (m, 2H), 3.20-3.05(m, 3H), 3.00-2.85 (m, 1H), 2.53 (t, J=11.0 Hz, 1H), 2.30-2.02 (m, 3H),1.85 (tdd, J=2.4, 4.6, 13.2 Hz, 1H). Data for Example 108, P-2: SFC(Method 105) RT=2.85 min; LC/MS (Method O): RT=2.182 min, (M+H)+=423.2;¹H NMR (400 MHz, methanol-d₄) δ=7.34-7.07 (m, 5H), 6.76 (d, J=8.5 Hz,2H), 4.53-4.39 (m, 2H), 3.69 (t, J=9.0 Hz, 1H), 3.46-3.38 (m, 1H),3.30-3.24 (m, 2H), 3.02-2.83 (m, 3H), 2.73-2.59 (m, 1H), 2.29-2.03 (m,3H), 1.88-1.79 (m, 1H).

Example 1091-(3,4-Dichlorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

The titled compound of example 109 was prepared as a mixture ofdiastereomers using the general procedure D. Data for Example 109: LC/MSRT=1.833 min, (M+H)+=454.9; ¹H NMR (400 MHz, DMSO-d₆) δ=9.31 (s, 1H),7.62 (dd, J=1.5, 8.0 Hz, 2H), 7.51 (d, J=1.5 Hz, 1H), 7.23 (dd, J=2.0,8.0 Hz, 1H), 7.09 (d, J=8.5 Hz, 2H), 6.72 (d, J=8.5 Hz, 2H), 4.39 (s,2H), 4.09 (q, J=5.5 Hz, 1H), 3.23-3.13 (m, 4H), 2.94-2.83 (m, 1H),2.43-2.34 (m, 1H), 2.21-2.09 (m, 2H), 2.01-1.70 (m, 3H).

Example 1103-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-(trifluoromethyl)benzyl)-pyrrolidin-2-one

The titled compound of example 110 was prepared as a mixture ofdiastereomers using the general procedure D. Data for Example 110: LC/MSRT=1.789 min, (M+H)+=455.0; ¹H NMR (400 MHz, methanol-d₄) δ=7.69 (d,J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.79-6.73(m, 2H), 4.60 (s, 2H), 3.81 (s, 2H), 3.77-3.68 (m, 1H), 3.46-3.40 (m,1H), 3.30-3.26 (m, 1H), 3.21-3.09 (m, 2H), 3.02-2.86 (m, 2H), 2.74-2.51(m, 1H), 2.06 (s, 3H), 1.90-1.80 (m, 1H).

Example 1111-(3-Chloro-4-fluorobenzyl)-3-(3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

The titled compound of example 110 was prepared as a mixture ofdiastereomers using the general procedure D. Data for Example 110: LC/MSRT=1.744 min, (M+H)+=439.0; ¹H NMR (400 MHz, methanol-d₄) δ=7.47-7.41(m, 1H), 7.28-7.24 (m, 2H), 7.18-7.12 (m, 2H), 6.76 (d, J=9.0 Hz, 2H),4.52-4.39 (m, 2H), 3.70 (q, J=9.4 Hz, 1H), 3.45-3.37 (m, 1H), 3.30-3.25(m, 1H), 3.21-3.08 (m, 2H), 3.01-2.85 (m, 2H), 2.69 (d, J=10.5 Hz, 1H),2.53 (t, J=11.3 Hz, 1H), 2.30-2.03 (m, 3H), 1.85 (tdd, J=2.3, 4.8, 13.2Hz, 1H).

Example 112 (Peak-1)(R)-3-((3S,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

and Example 112 (Peak-2)(R)-3-((3R,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

Step A. (S)-3-((tert-Butyldimethylsilyl)oxy)pyrrolidin-2-one

A stirred solution of commercial (S)-3-hydroxypyrrolidin-2-one (5 g, 50mmol) in DCM (198 ml) was treated with DMAP (0.2 g, 1.63 mmol),imidazole (6.73 g, 99 mmol), and TBDMS-Cl (8.94 g, 59 mmol). Thereaction mixture was stirred at rt for 16h, and then was washed with asatd. NaHCO₃ solution. The organic layer was concentrated and the crudereaction product was purified by silica gel chromatography, eluting with50% ethyl acetate in petroleum ether. The desired product was isolatedas a white solid (8.1 g, 76%). LC/MS (M+H)+=216.2; ¹H NMR (400 MHz,chloroform-d) δ 6.40 (br. s., 1H), 4.26 (t, J=7.8 Hz, 1H), 3.42-3.34 (m,1H), 3.29-3.21 (m, 1H), 2.36 (dtd, J=12.7, 7.3, 3.3 Hz, 1H), 2.07-1.96(m, 1H), 0.91 (s, 9H), 0.15 (d, J=7.0 Hz, 6H).

Step B.(S)-3-((tert-Butyldimethylsilyl)oxy)-1-(4-methylbenzyl)pyrrolidin-2-one

(S)-3-((tert-Butyldimethylsilyl)oxy)pyrrolidin-2-one (5 g, 23.22 mmol)was dissolved in anhydrous THF (46.4 ml) and the reaction mixture wascooled to 0° C. under a nitrogen atmosphere. Sodium hydride (1.393 g,34.8 mmol) was then added in one portion and the reaction mixture wasallowed to stir for 5 min before the dropwise addition of1-(bromomethyl)-4-methylbenzene (5.37 g, 29 mmol) in anhydrous THF (46ml). The reaction was allowed to stir at 0° C. for 5 min, then thecooling bath was removed and mixture was allowed to warm to rtovernight. The reaction was cautiously quenched with water (100 mL) andthen extracted with ethyl acetate (3×100 mL). The combined organiclayers were then washed with brine (200 mL) and dried (MgSO4).Evaporation of the solvent in vacuo gave the crude product (9.6 g, oil)which was then purified by silica gel chromatography (330 g of silica)eluting with a gradient of 0% to 20% ethyl acetate in hexanes to provide6.53 g (88%) of the desired product. LC/MS (Conditions B) RT=4.320 min,(M+H)+=320.3; ¹H NMR (400 MHz, chloroform-d) δ 7.15 (s, 4H), 4.42 (s,2H), 4.37 (t, J=7.6 Hz, 1H), 3.32-3.18 (m, 1H), 3.10 (dt, J=9.7, 7.5 Hz,1H), 2.36 (s, 3H), 2.29 (dtd, J=12.6, 7.6, 3.1 Hz, 1H), 1.97-1.84 (m,1H), 0.95 (s, 9H), 0.20 (d, J=10.3 Hz, 6H).

Step C. (S)-3-Hydroxy-1-(4-methylbenzyl)pyrrolidin-2-one

HCl (4 M in 1,4-dioxane, 25.5 ml, 102 mmol) was added in one portion toa solution of(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-methylbenzyl)pyrrolidin-2-one(6.53 g, 20.4 mmol) in anhydrous DCM (20.44 ml) at rt. A slight exothermwas noted. The reaction mixture was allowed to stir at rt for 2 h andthen evaporated in vacuo. The residue was taken up in DCM (100 mL) andwashed with a satd. sodium bicarbonate solution (100 mL) and brine (50mL), and then the solution was dried over MgSO4 and concentrated to aresidue. The crude product was purified by silica gel chromatography(120 g of silica) eluting with a gradient of 40% to 100% ethyl acetatein hexanes to provide 3.73 g (89%) of the desired product. LC/MS(Conditions B) RT=2.338 min, (M+H)+=206.2; ¹H NMR (400 MHz,chloroform-d) δ 7.26-7.02 (m, 4H), 4.43 (d, J=3.5 Hz, 2H), 4.41-4.37 (m,1H), 3.66 (d, J=2.6 Hz, 1H), 3.34-3.05 (m, 2H), 2.41 (dddd, J=12.8, 8.4,6.6, 2.2 Hz, 1H), 2.34 (s, 3H), 1.93 (dq, J=12.8, 8.8 Hz, 1H).

Step D. (S)-1-(4-Methylbenzyl)-2-oxopyrrolidin-3-yl methanesulfonate

Triethylamine (0.51 ml, 3.6 mmol) was added to a cooled solution of(S)-3-hydroxy-1-(4-methylbenzyl)pyrrolidin-2-one (0.5 g, 2.4 mmol) inanhydrous DCM (12.2 ml) at 0° C. under a nitrogen atmosphere.Methanesulfonyl chloride (0.2 ml, 2.6 mmol) was then added dropwise andthe reaction was allowed to stir at 0° C. for 15 min before quenchingwith a satd. sodium bicarbonate solution (10 mL). The mixture wasallowed to warm to rt and the aqueous layer was separated and extractedwith DCM (2×). The combined organic layers were dried over MgSO₄ andevaporated in vacuo to give a white solid (0.73 g) which was thenpurified by silica gel chromatography (40 g of silica) eluting with agradient of 0% to 50% ethyl acetate in hexanes to provide 0.63 g (91%)of the desired product as a white solid.

Step E. cis-tert-Butyl4-(4-(benzyloxy)phenyl)-3-fluoro-4-hydroxypiperidine-1-carboxylate

To a cloudy solution of tert-butyl4-(4-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (Example50, step C, 2.8 g, 7.7 mmol) in acetonitrile (30 mL) and water (8 mL)was added 1.2 eq. of Selectfluor at rt. After stirring at rt for 1 h,another 0.5 eq. of Selectfluor was added, and the mixture was stirred at50° C. for 30 min. A saturated NaHCO₃ solution (100 mL) was added andthe mixture was extracted with 3×150 mL of EtOAc. The combined organiclayers were concentrated. The residue was dissolved in 20 mL of CH₂Cl₂.Triethylamine (3.20 mL, 23 mmol) was added followed bydi-tertbutyldicarbonate (4.45 mL, 19.15 mmol). The mixture was stirredat rt for 2 h, and then the mixture was concentrated. The residue waspurified via silica gel chromatography (80 g of silica) eluting with agradient of 0 to 100% ethyl acetate in hexanes. The first eluting spotwas isolated to give cis-tert-butyl4-(4-(benzyloxy)phenyl)-3-fluoro-4-hydroxypiperidine-1-carboxylate (2.0g, 5 mmol, 65% yield). LC/MS (Conditions CZ-1, M-t-butyl+AcCN+H)⁺=387.2.(M-t-butyl+AcCN)+=369.25. RT 1.392 min; ¹H NMR (500 MHz, chloroform-d) δ7.55-7.31 (m, 7H), 7.09-6.90 (m, 2H), 5.09 (s, 2H), 5.05-4.93 (m, 1H),4.89 (br. s., 1H), 4.31 (br. s., 1H), 3.92 (br. s., 1H), 3.29 (br. s.,1H), 3.25-3.04 (m, 1H), 2.00-1.86 (m, 1H), 1.83 (br. s., 1H), 1.55-1.45(m, 9H).

Step F. tert-Butyl4-(4-(benzyloxy)phenyl)-5-fluoro-5,6-dihydropyridine-1(2H)-carboxylate

To a solution of cis-tert-butyl4-(4-(benzyloxy)phenyl)-3-fluoro-4-hydroxypiperidine-1-carboxylate (2.0g, 5 mmol) in CH₂Cl₂ (25 mL) was added 6 mL of TFA dropwise at rt. Themixture was stirred at rt for 2 h. Another 8 mL of TFA was added. Afterstirring for 1 h, 3 mL more of TFA was added. The mixture wasconcentrated to dryness in vacuo at rt, then 10 mL of CH₂Cl₂ and Et₃N(4.2 mL, 30 mmol) were added followed by bis-(tert)butyldicarbonate (3.5mL, 15 mmol) and the resulting mixture was stirred for 16 h. The mixturewas concentrated and directly purified via silica gel chromatography (40g of silica) eluting with a gradient of 0-20% ethyl acetate in hexanesto provide racemic tert-butyl4-(4-(benzyloxy)phenyl)-5-fluoro-5,6-dihydropyridine-1(2H)-carboxylate(1.35 g, 3.5 mmol, 70.7% yield), LC/MS (Conditions CZ-1,M-Boc+AcCN+H)+=325.25. (M-t-butyl+AcCN+H)+=369.25. RT 1.504 min; ¹H NMR(500 MHz, chloroform-d) δ 7.48-7.38 (m, 6H), 7.38-7.32 (m, 1H), 6.99 (d,J=8.8 Hz, 2H), 6.34-6.16 (m, 1H), 5.45-5.20 (m, 1H), 5.10 (s, 2H),4.61-4.37 (m, 2H), 3.81 (br. s., 1H), 3.39-3.24 (m, 1H), 1.59 (s, 3H),1.52 (s, 9H).

Step G. cis-tert-Butyl4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate

To 10% Pd/C (220 mg) under nitrogen was added a soln of tert-butyl4-(4-(benzyloxy)-phenyl)-5-fluoro-5,6-dihydropyridine-1(2H)-carboxylate(1.35 g, 3.5 mmol) in ethyl acetate (20 mL). The mixture was stirred atrt under a hydrogen atmosphere at balloon pressure for 45 min. The Pd/Cwas removed by filtration, and the filtrate was concentrated. Theresidue was purified via silica gel chromatography (40 g of silica gel)eluting with a gradient of 0-100% ethyl acetate in hexanes to give theproduct cis-tert-butyl4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (1.05 g, 2.7mmol, 77% yield). LC/MS (Conditions CZ-1) (M-t-butyl, AcCN+H)+=371.25.RT=1.504 min; ¹H NMR (500 MHz, chloroform-d) δ 7.45 (d, J=7.6 Hz, 2H),7.40 (t, J=7.5 Hz, 2H), 7.34 (t, J=7.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H),6.96 (ddd, J=8.9, 2.7, 2.0 Hz, 2H), 5.07 (s, 2H), 4.79-4.60 (m, 1H),4.55-4.23 (m, 2H), 3.08-2.81 (m, 2H), 2.75 (ddd, J=36.0, 13.4, 3.1 Hz,1H), 2.21 (qd, J=12.9, 4.3 Hz, 1H), 1.69 (d, J=11.7 Hz, 1H), 1.59 (s,3H), 1.51 (s, 9H). The structure of this compound was verified bysingle-crystal X-ray analysis.

Step H. cis-4-(4-(Benzyloxy)phenyl)-3-fluoropiperidine

To a solution of cis-tert-butyl4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate (400 mg, 1.04mmol) in CH₂Cl₂ (4 mL) was dropwise added TFA (1 mL, 13 mmol) at rt. Themixture was stirred at rt for 2 h and then concentrated. To the residuewas added 50 mL of saturated aqueous sodium bicarbonate and the mixturewas extracted with 3×60 mL of CH₂Cl₂. The organic layer was dried overNa₂SO₄, filtered, and concentrated to dryness to yield 270 mgcis-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine (0.95 mmol, 91%).(M+H)⁺=286.25. ¹H NMR (500 MHz, chloroform-d) δ 7.49-7.38 (m, 4H), 7.34(t, J=7.5 Hz, 1H), 7.26-7.20 (m, J=8.5 Hz, 2H), 7.01-6.93 (m, 2H), 5.08(s, 2H), 4.70 (d, J=49.0 Hz, 1H), 3.38 (t, J=12.5 Hz, 1H), 3.25 (dt,J=13.4, 2.0 Hz, 1H), 2.93 (d, J=14.3 Hz, 1H), 2.90-2.68 (m, 3H), 2.09(qd, J=12.9, 4.1 Hz, 1H), 1.69 (d, J=14.3 Hz, 1H).

Step I. cis-4-(3-Fluoropiperidin-4-yl)phenol

To 10% Pd/C (40 mg) under nitrogen was added a solution ofcis-4-(4-(benzyloxy)phenyl)-3-fluoropiperidine (140 mg, 0.49 mmol) inIPA (4 mL). The mixture was stirred under a hydrogen atmosphere usingballoon pressure at rt for 2 h. The Pd/C was removed by filtrationthrough a glass fiber filter. The filtrate was concentrated to givecis-4-(3-fluoropiperidin-4-yl)phenol (90 mg, 0.46 mmol, 94% yield).LC/MS (Method J, M+H)⁺=196.25, RT=0.706 min; ¹H NMR (500 MHz,methanol-d₄) δ 7.14 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.7 Hz, 2H), 4.63 (d,J=48.4 Hz, 1H), 3.30-3.22 (m, 1H), 3.15 (dt, J=13.1, 2.0 Hz, 1H),2.95-2.66 (m, 3H), 2.12 (qd, J=13.0, 4.2 Hz, 1H), 1.64 (dd, J=13.4, 3.0Hz, 1H).

Step J.(R)-3-((3S,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-oneand(R)-3-((3R,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

To a solution of cis-4-(3-fluoropiperidin-4-yl)phenol (60 mg, 0.31 mmol)in 1.0 mL of CH₃CN and DIPEA (0.2 mL, 1.2 mmol) at 80° C. was added asolution of (S)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl methanesulfonate(87 mg, 0.3 mmol) in 0.5 mL of CH₃CN over 1.5 h. The mixture was thenstirred at 80° C. for 16 h. The mixture was allowed to cool to rt andthen concentrated. The residue was purified via silica gelchromatography (4 g of silica) eluting with a gradient of 0-100% EtOAcin hexanes to give a mixture of two diastereomers, which were furtherseparated via chiral HPLC under the following conditions: Chiralcel ODcolumn (21×250 mm, 10μ) eluting with an isocratic mixture of 30% B wheresolvent A=0.1% diethylamine in n-heptane and solvent B=100% ethanol. Theabsolute stereochemistry of the 2 products has not been assigned and isshown and named for convenience. The first eluting isomer (Example 112,P-1) was(R)-3-((3S,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one(33.8 mg, 0.086 mmol, 28% yield). ¹H NMR (500 MHz, methanol-d₄) δ7.21-7.07 (m, 6H), 6.78-6.68 (m, 2H), 4.70 (d, J=48.8 Hz, 1H), 4.41 (dd,J=58.0, 14.5 Hz, 2H), 3.61 (t, J=8.8 Hz, 1H), 3.30-3.03 (m, 5H),2.77-2.60 (m, 1H), 2.51 (t, J=11.1 Hz, 1H), 2.32 (s, 3H), 2.31-2.15 (m,2H), 2.01 (dq, J=13.2, 8.4 Hz, 1H), 1.69 (dd, J=13.1, 2.6 Hz, 1H),(M+H)+=383.25. HPLC RT under separation conditions=8.87 min. The secondeluting isomer (Example 112, P-2) was(R)-3-((3R,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one(35.2 mg, 0.084 mmol, 27.3% yield), ¹H NMR (500 MHz, methanol-d₄) δ7.19-7.08 (m, 6H), 6.74 (d, J=8.4 Hz, 2H), 4.66 (d, J=47.9 Hz, 1H), 4.41(dd, J=53.7, 14.8 Hz, 2H), 3.58 (t, J=8.8 Hz, 1H), 3.42 (t, J=10.8 Hz,1H), 3.30-3.14 (m, 2H), 3.05-2.88 (m, 2H), 2.79-2.51 (m, 2H), 2.33 (s,3H), 2.31-2.13 (m, 2H), 2.06-1.90 (m, 1H), 1.67 (d, J=10.8 Hz, 1H),(M+H)+=383.25. HPLC RT under separation conditions=11.97 min.

Example 1131-(4-fluorobenzyl)-3-(4-(4-hydroxyphenyl)piperazin-1-yl)pyrrolidin-2-one

A mixture of intermediate 1 (150 mg), 4-(piperazin-1-yl)phenol (262 mg),and triethylamine (0.820 mL) in acetonitrile (10 mL) was heated in asealed vial at 145° C. for 1 h. The crude reaction was allowed to coolto rt and was diluted with dichloromethane (2 mL). The crude mixture waspurified using silica gel column chromatography (50-100% ethylacetate/hexanes, then 10% methanol/ethyl acetate) to afford1-(4-fluorobenzyl)-3-(4-(4-hydroxyphenyl)piperazin-1-yl)pyrrolidin-2-one(300 mg, 54% yield) as a light brown powder. LC/MS (M+H)+=351.3; ¹H NMR(500 MHz, DMSO-d₆) δ 9.10 (s, 1H), 7.77-7.56 (m, 2H), 7.47-7.30 (m, 2H),7.19-7.08 (m, 1H), 6.94 (d, J=8.4 Hz, 2H), 6.70-6.59 (m, 2H), 3.76-3.66(m, 2H), 3.58 (t, J=9.0 Hz, 1H), 2.95 (d, J=11.1 Hz, 1H), 2.71 (d,J=11.0 Hz, 1H), 2.58-2.52 (m, 1H), 2.38 (d, J=7.0 Hz, 2H), 2.26-2.10 (m,2H), 2.05-1.95 (m, 1H), 1.54 (t, J=7.9 Hz, 2H), 1.46-1.30 (m, 1H),1.21-1.02 (m, 2H).

Example 114 (Peak-1)(R)-1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

and Example 114 (Peak-2)(S)-1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Step A. (S)-3-(tert-Butyldimethylsilyloxy)pyrrolidin-2-one

4-Dimethylaminopyridine (0.199 g, 1.63 mmol), imidazole (6.73 g, 99mmol) and TBDMS-Cl (20.6 ml, 59.3 mmol) was added to a stirred solutionof (S)-3-hydroxypyrrolidin-2-one (5.0 g, 49.5 mmol) in DCM (198 ml) atRT. The reaction mixture was stirred for 24 h and then diluted withwater. The mixture was extracted with DCM. The combined organic layerswere washed with saturated aqueous sodium bicarbonate solution, driedover sodium sulfate, filtered and concentrated in vacuo. The crudeproduct was purified using silica gel column chromatography (50-80%EtOAc/hexanes) to afford(S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (10.4 g, 97% yield)as a white solid: ¹H NMR (500 MHz, chloroform-d) δ 6.15 (br. s., 1H),4.28 (t, J=7.6 Hz, 1H), 3.40 (dddd, J=9.7, 8.5, 3.1, 1.2 Hz, 1H), 3.28(dt, J=9.6, 7.4 Hz, 1H), 2.39 (dtd, J=12.7, 7.3, 3.1 Hz, 1H), 2.10-2.02(m, 1H), 0.97-0.92 (m, 9H), 0.20-0.14 (m, 6H).

Step B.(S)-3-(tert-Butyldimethylsilyloxy)-1-(4-(difluoromethyl)benzyl)pyrrolidin-2-one

A 60% dispersion of sodium hydride in mineral oil (232 mg, 5.31 mmol)was added to a stirred solution of(S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (762 mg, 3.54 mmol)in THF (7 mL) at 0° C. After 15 min, a solution of1-(bromomethyl)-4-(difluoromethyl)benzene (980 mg, 4.43 mmol) in THF (7mL) was added to the reaction mixture. The resulting mixture was stirredat RT for 6 h. The reaction was quenched with pellets of ice. Theresulting mixture was extracted with EtOAc. The combined organic layerswere washed with water, dried over sodium sulfate, filtered andconcentrated in vacuo. The crude reaction mixture was purified usingsilica gel column chromatography (0-30% EtOAc/hexanes) to afford(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-(difluoromethyl)benzyl)pyrrolidin-2-one(440 mg, 35% yield) as a white solid: LCMS (M+H)+356.3; ¹H NMR (500 MHz,chloroform-d) δ 7.49 (d, J=8.1 Hz, 2H), 7.35 (d, J=7.9 Hz, 2H), 6.65(br. t, J=1.0 Hz, 1H), 4.56-4.44 (m, 2H), 4.38 (t, J=7.5 Hz, 1H), 3.27(ddd, J=9.7, 8.7, 3.4 Hz, 1H), 3.13 (dt, J=9.7, 7.4 Hz, 1H), 2.36-2.27(m, 1H), 1.98-1.90 (m, 1H), 0.96 (br. s., 9H), 0.22-0.20 (m, 3H),0.20-0.18 (m, 3H).

Step C. (S)-1-(4-(Difluoromethyl)benzyl)-3-hydroxypyrrolidin-2-one

A solution of 4 M HCl in dioxane (0.62 mL, 2.5 mmol) was added to astirred solution of(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-(difluoromethyl)benzyl)pyrrolidin-2-one(440 mg, 1.24 mmol) in dichloromethane (1.24 mL) at RT. The reactionmixture was stirred for 2 h. The reaction mixture was concentrated invacuo to afford(S)-1-(4-(difluoromethyl)benzyl)-3-hydroxypyrrolidin-2-one (368 mg,quantitative yield): LC-MS (M+H)+242.1.

Step D. (S)-1-(4-(Difluoromethyl)benzyl)-2-oxopyrrolidin-3-ylmethanesulfonate

Triethylamine (0.319 mL, 2.29 mmol) and methansulfonyl chloride (0.131mL, 1.68 mmol) was added to a stirred solution of(S)-1-(4-(difluoromethyl)benzyl)-3-hydroxypyrrolidin-2-one (368 mg, 1.53mmol) in dichloromethane (7.63 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 1 h. The resulting mixture was diluted with waterand the aqueous mixture was extracted with dichloromethane. The combinedorganic layers were washed with 10% sodium bicarbonate solution, driedover sodium sulfate, filtered, and concentrated in vacuo. The crudematerial was purified using silica gel column chromatography (0-100%EtOAc). The pure fractions were combined and concentrated in vacuo toafford 1-(4-(difluoromethyl)benzyl)-2-oxopyrrolidin-3-ylmethanesulfonate (322 mg, 66% yield) as a white solid: LC-MS(M+H)+320.1; ¹H NMR (500 MHz, chloroform-d) δ 7.53 (d, J=7.9 Hz, 2H),7.38-7.33 (m, 2H), 6.67 (br. t, J=1.0 Hz, 1H), 5.27 (dd, J=8.2, 7.5 Hz,1H), 4.60-4.49 (m, 2H), 3.41-3.35 (m, 1H), 3.33 (s, 3H), 3.27 (dt,J=9.9, 7.3 Hz, 1H), 2.64-2.55 (m, 1H), 2.27 (ddt, J=13.9, 8.9, 7.1 Hz,1H).

Step E.(R)-1-(4-(Difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(Peak 1) and(S)-1-(4-(Difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(Peak 2)

A solution of (S)-1-(4-(difluoromethyl)benzyl)-2-oxopyrrolidin-3-ylmethanesulfonate (500 mg, 1.57 mmol) in 5.0 mL of acetonitrile was addeddropwise over 1.5 h to a stirred mixture of4-((3S,4S)-3-fluoropiperidin-4-yl)phenol, hydrochloride (363 mg, 1.57mmol, from example 46, step M) and N,N-diisopropylethylamine (1.09 mL,6.26 mmol) in 5.0 mL of acetonitrile maintained at 85° C. After completeaddition, the reaction mixture was stirred at 85° C. for 16 h. Theresulting mixture was concentrated in vacuo. The residue was purifiedusing silica gel column chromatography (0-100% EtOAc/hexanes) to afforda diastereomeric mixture of1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(235 mg, 35% yield) due to partial epimerization. A sample of thediastereomeric mixture (780 mg) was separated by preparative chiral SFC(column=Lux Cellulose-2 (21×250 mm, 5 μm); isocratic solvent=20%methanol (with 15 mM ammonia)/80% CO₂; temp=35° C.; flow rate=60 mL/min;injection volume=1.0 mL (˜20 mg/mL in MeOH) stacked @ 13 min intervals;λ=210 nM; Peak 1=19.6 min, Peak 2=24.5 min) to afford 389 mg of Example114, P-1 and 242 mg of Example 114, P-2. Data for Example 114, P-1:LC-MS m/z 419.3 (M+H⁺); ¹H NMR (500 MHz, chloroform-d) δ 7.50 (d, J=7.9Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.91-6.80 (m,2H), 6.65 (t, J=56.4 Hz, 1H), 4.96 (s, 1H), 4.77-4.43 (m, 3H), 3.68 (t,J=8.8 Hz, 1H), 3.42-3.33 (m, 1H), 3.29-3.14 (m, 2H), 2.85 (d, J=10.4 Hz,1H), 2.78-2.69 (m, 1H), 2.69-2.57 (m, 1H), 2.48 (td, J=9.9, 4.9 Hz, 1H),2.21-2.11 (m, 1H), 2.04 (dq, J=13.0, 8.6 Hz, 1H), 1.94-1.82 (m, 2H)).The relative and absolute configuration of Example 114, P-1 wasconfirmed by single crystal X-ray analysis. Data for Example 114, P-2:LC-MS m/z 419.3 (M+H⁺); ¹H NMR (500 MHz, chloroform-d) δ 7.50 (d, J=7.9Hz, 2H), 7.35 (d, J=7.9 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.87-6.81 (m,2H), 6.65 (t, J=56.5 Hz, 1H), 4.95 (s, 1H), 4.74-4.42 (m, 3H), 3.66 (t,J=8.9 Hz, 1H), 3.28-3.15 (m, 3H), 3.07-2.99 (m, 1H), 2.72-2.58 (m, 2H),2.49-2.40 (m, 1H), 2.20-2.12 (m, 1H), 2.04 (dq, J=13.0, 8.7 Hz, 1H),1.93-1.87 (m, 2H).

Example 115(R)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

Step A. tert-Butyl4-(4-(benzyloxy)-3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate

A solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (5.0 g, 17.8 mmol)and tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(6.60 g, 21.3 mmol) in acetonitrile (50 mL) was degassed for 5 min. Tothis was added water (50 mL), Na₂CO₃ (5.66 g, 53.4 mmol) and Pd(Ph₃P)₄(1.23 g, 1.07 mmol) and the reaction was further degassed for 10 min. Itwas then heated to 80° C. for 16 h. The reaction cooled to rt, pouredinto water, and extracted with EtOAc. The combined organic layers were,dried with magnesium sulfate, filtered through celite, and concentratedin vacuo to afford a brown oil. The oil was purified using silica gelcolumn chromatography (0-30% EtOAc/hexanes) to afford 1-butyl4-(4-(benzyloxy)-3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate(5.63 g, 83% yield): LC-MS [M+H]⁺-tBu+ACN=369.2; ¹H NMR (500 MHz,DMSO-d₆) δ 7.51-7.27 (m, 6H), 7.25-7.13 (m, 2H), 6.12 (br. s., 1H), 5.19(s, 2H), 3.97 (br. s., 2H), 3.51 (t, J=5.6 Hz, 2H), 2.41 (d, J=1.5 Hz,2H), 1.42 (s, 9H).

Step B. (±)-rel-(3R,4R)-tert-Butyl4-(4-(benzyloxy)-3-fluorophenyl)-3-hydroxypiperidine-1-carboxylate

To sodium borohydride (2.282 g, 60.3 mmol) in THF (81 ml) at 0° C. wasadded boron trifluoride diethyl etherate (9.86 ml, 78 mmol) dropwise viaaddition funnel. The ice bath was removed and the solution was allowedto warm to rt and stir for 1 h. The reaction was chilled to 0° C., thentert-butyl4-(4-(benzyloxy)-3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate(7.46 g, 19.5 mmol) in THF (8.11 ml) was added dropwise via additionalfunnel. After complete addition, the reaction was allowed to warm to rtand was stirred for 2 h. The reaction was cooled to 0° C. and quenchedwith water (16.2 ml) until the effervescence subsided. To this mixturewas sequentially added aqueous 10% sodium hydroxide (14.2 ml, 38.9mmol), aqueous 30% hydrogen peroxide (13.91 ml, 136 mmol) and EtOH (16.2ml). The resulting mixture was stirred at rt for 16 h. The mixture wasdiluted with ice water and extracted with dichloromethane. The combinedorganic layers were dried with magnesium sulfate, filtered, andconcentrated in vacuo to afford (±)-rel-(3R,4R)-tert-butyl4-(4-(benzyloxy)-3-fluorophenyl)-3-hydroxypiperidine-1-carboxylate (7.32g, 94% yield) as a white solid: LC-MS [M+H]+=328.2; ¹H NMR (500 MHz,DMSO-d₆) δ 7.53-7.28 (m, 5H), 7.18-7.07 (m, 2H), 6.97 (d, J=8.2 Hz, 1H),5.14 (s, 2H), 4.82 (d, J=5.6 Hz, 1H), 4.10 (br. s., 1H), 3.95 (br. s.,1H), 3.40 (tt, J=10.2, 5.2 Hz, 1H), 2.81-2.60 (m, 1H), 2.46-2.35 (m,1H), 1.66 (dd, J=13.4, 3.1 Hz, 1H), 1.59-1.46 (m, 1H), 1.42 (s, 9H).

Step C. (3R,4R)-tert-Butyl4-(4-(benzyloxy)-3-fluorophenyl)-3-hydroxypiperidine-1-carboxylate and(3S,4S)-tert-Butyl4-(4-(benzyloxy)-3-fluorophenyl)-3-hydroxypiperidine-1-carboxylate

(±)-rel-(3R,4R)-tert-Butyl4-(4-(benzyloxy)-3-fluorophenyl)-3-hydroxypiperidine-1-carboxylate (17.1g, from step B) was subjected to chiral SFC separation (column=ChiralpakAD-H; isocratic solvent=30% methanol/70% CO₂; temp=40° C.; flow rate=3mL/min; λ=220 nM; Peak 1 (E-1)=3.8 min, Peak 2 (E-2)=7.7 min) to yieldenantiomers E-1 (7.2 g, 42% yield) and E-2 (7.5 g, 44% yield). Data forE-1: LC-MS [M+H]+-t-Bu=346.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.52-7.26 (m,5H), 7.18-7.06 (m, 2H), 6.97 (d, J=8.4 Hz, 1H), 5.14 (s, 2H), 4.81 (d,J=5.6 Hz, 1H), 4.09 (br. s., 1H), 3.95 (br. s., 1H), 3.39 (td, J=10.3,5.3 Hz, 1H), 2.47-2.30 (m, 3H), 1.72-1.62 (m, 1H), 1.59-1.45 (m, 1H),1.42 (s, 9H). Data for E-2: LC-MS [M+H]+-t-Bu=346.1; ¹H NMR (500 MHz,DMSO-d₆) δ 7.52-7.27 (m, 5H), 7.19-7.06 (m, 2H), 6.97 (dd, J=8.4, 1.1Hz, 1H), 5.14 (s, 2H), 4.81 (d, J=5.6 Hz, 1H), 4.10 (br. s., 1H), 3.95(br. s., 1H), 3.49-3.35 (m, 1H), 2.46-2.33 (m, 3H), 1.72-1.63 (m, 1H),1.59-1.46 (m, 1H), 1.46-1.32 (m, 9H).

Step D. (3S,4S)-tert-Butyl4-(3-fluoro-4-hydroxyphenyl)-3-hydroxypiperidine-1-carboxylate

To (3S,4S)-tert-butyl4-(4-(benzyloxy)-3-fluorophenyl)-3-hydroxypiperidine-1-carboxylate (4.0g, 9.96 mmol, E-2 from step C) in degassed MeOH (100 mL) was added 10%Pd/C (0.191 g, 1.79 mmol) and the reaction was repeated evacuated andflushed with hydrogen gas. Then placed under 1 atm of hydrogen for 4 h.The reaction solution was purged with nitrogen and filtered throughcelite. The filtrated was concentrated to afford (3S,4S)-tert-butyl4-(3-fluoro-4-hydroxyphenyl)-3-hydroxypiperidine-1-carboxylate (2.99 g,96% yield) as a grey oil. LC-MS [M+H]⁺-tBu=256.05; ¹H NMR (500 MHz,DMSO-d₆) δ 7.03-6.95 (m, 1H), 6.89-6.78 (m, 2H), 4.78 (d, J=4.6 Hz, 1H),4.09 (br. s., 2H), 3.94 (br. s., 1H), 3.36 (dd, J=9.5, 4.7 Hz, 1H), 3.17(s, 1H), 2.80-2.58 (m, 1H), 2.42-2.27 (m, 1H), 1.65 (dd, J=13.4, 3.4 Hz,1H), 1.56-1.33 (m, 10H).

Step E. (3S,4S)-tert-Butyl3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate

To (3S,4S)-tert-butyl4-(3-fluoro-4-hydroxyphenyl)-3-hydroxypiperidine-1-carboxylate (2.99 g,9.60 mmol) in DCM (75 mL) at 0° C. was added DAST (6.34 mL, 48.0 mmol)dropwise. The reaction was then allowed to warm to room temperature andstir for 2 h. The reaction was slowly quenched with ice water. Thereaction was then extracted with dichloromethane, washed with additionalwater, dried with magnesium sulfate, filtered and concentrated in vacuoto afford (3S,4S)-tert-butyl3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate (3.88 g,quantitative yield) as a yellow viscous oil: LC-MS [M−H]+312.2; ¹H NMR(500 MHz, DMSO-d₆) δ 7.22-7.10 (m, 1H), 7.00-6.76 (m, 3H), 5.76 (s, 2H),4.60 (td, J=10.1, 5.2 Hz, 1H), 4.50 (td, J=10.1, 5.2 Hz, 1H), 4.27 (br.s., 1H), 4.07-3.78 (m, 2H), 3.66-3.50 (m, 1H), 3.00-2.65 (m, 4H),1.81-1.69 (m, 1H), 1.63-1.50 (m, 1H), 1.46-1.30 (m, 14H), 1.20-1.01 (m,2H).

Step E. (3S,4S)-tert-Butyl3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate

To (3S,4S)-tert-butyl3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidine-1-carboxylate (3.01 g,9.61 mmol) in dioxane (10 mL) was added HCl (4 M in Dioxane) (24 mL, 96mmol) and the reaction was allowed to stir at room temperature for 5 h.The reaction was concentrated to an oil. The oil was taken up insaturated aqueous sodium bicarbonate and extracted with EtOAc/5% MeOH.The combined organic layers were concentrated in vacuo to afford2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (2.15 g, quantitativeyield): LC-MS [M+H]+=214.1; ¹H NMR (500 MHz, DMSO-d₆) δ 6.93 (d, J=12.4Hz, 1H), 6.85-6.72 (m, 2H), 4.49 (td, J=9.9, 4.9 Hz, 1H), 4.39 (td,J=10.0, 5.0 Hz, 1H), 3.27-3.19 (m, 3H), 2.85 (d, J=11.4 Hz, 2H),2.62-2.54 (m, 2H), 2.46-2.37 (m, 4H), 1.76-1.64 (m, 2H), 1.57-1.37 (m,3H).

Step F. (R)-3-((3S,4S)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl) pyrrolidin-2-one

A solution of (S)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-ylmethanesulfonate (0.106 g, 0.375 mmol, from example 112, step D) inacetonitrile (1 mL) was added to a mixture of2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (0.04 g, 0.188 mmol,from step E) and DIPEA (0.098 mL, 0.563 mmol) in acetonitrile (2 mL)heated at 80° C. The reaction mixture was then stirred at 80° C. for 16h. The mixture was allowed to cool to rt and then concentrated in vacuo.The residue was purified using preparative LC/MS (Waters XBridge C18,19×150 mm, 5 μm; Guard Column: Waters XBridge C18, 19×10 mm, 5 μm;Mobile Phase A: 5:95 acetonitrile:water with 10 mM NH₄OAc; Mobile PhaseB: 95:5 acetonitrile:water with 10 mM NH₄OAc; Gradient: 15-60% B over 25min, followed by a 10 min hold at 60% B and 5 min hold at 100% B; Flow:15 mL/min). Fractions containing the desired product were combinedconcentrated in vacuo using a Genevac centrifugal evaporator to thetitled compound of Example 115 (31 mg, 0.077 mmol, 41% yield) as paleyellow solid. LC-MS (M+H)⁺401; ¹H NMR: (400 MHz, DMSO-d₆) d=7.19-7.06(m, 5H), 6.95-6.84 (m, 2H), 4.70-4.48 (m, 1H), 4.41-4.24 (m, 2H), 3.55(s, 1H), 3.48-3.29 (m, 3H), 2.76-2.63 (m, 2H), 2.62-2.52 (m, 1H), 2.28(s, 4H), 2.16-2.03 (m, 1H), 1.89 (s, 3H), 1.79-1.54 (m, 2H).

Example 116(R)-1-(4-chlorobenzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

Step A.(S)-3-(tert-Butyldimethylsilyloxy)-1-(4-chlorobenzyl)pyrrolidin-2-one

A 60% dispersion of sodium hydride in mineral oil (0.608 g, 13.9 mmol)was added to a stirred solution of(S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (2.0 g, 9.29 mmol,from example 114, step A) in THF (7 mL) at 0° C. After 15 min, asolution of 1-(bromomethyl)-4-chlorobenzene (1.72 g, 8.37 mmol) in THF(7 mL) was added to the reaction mixture. The resulting mixture wasstirred at RT for 6 h. The reaction was quenched with pellets of ice.The resulting mixture was extracted with EtOAc. The combined organiclayers were washed with water, dried over sodium sulfate, filtered andconcentrated in vacuo. The crude reaction mixture was purified usingsilica gel column chromatography (0-15% EtOAc/hexanes) to afford(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-chlorobenzyl)pyrrolidin-2-one(1.34 g, 42% yield): LCMS (M+H)⁺340.2; ¹H NMR (500 MHz, chloroform-d) δ¹H NMR (500 MHz, chloroform-d) δ 7.36-7.29 (m, J=8.4 Hz, 2H), 7.23-7.16(m, J=8.4 Hz, 2H), 4.51-4.33 (m, 3H), 3.31-3.22 (m, 1H), 3.11 (dt,J=9.7, 7.4 Hz, 1H), 2.37-2.25 (m, 1H), 1.97-1.84 (m, 1H), 0.95 (s, 9H),0.21 (s, 3H), 0.18 (s, 3H).

Step B. (S)-1-(4-Chlorobenzyl)-3-hydroxypyrrolidin-2-one

A solution of 4 M HCl in dioxane (4.93 ml, 19.7 mmol) was added to astirred solution of(S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-chlorobenzyl)pyrrolidin-2-one(1.34 g, 3.94 mmol) in dichloromethane (4 mL) at RT. The reactionmixture was stirred for 2 h. The reaction mixture was concentrated invacuo to afford (S)-1-(4-chlorobenzyl)-3-hydroxypyrrolidin-2-one (910mg, 4.03 mmol, quantitative yield): LC-MS (M+H)⁺226.1; ¹H NMR (500 MHz,methanol-d₄) δ 7.37-7.33 (m, J=8.5 Hz, 2H), 7.27-7.23 (m, J=8.5 Hz, 2H),4.52-4.37 (m, 2H), 4.34 (t, J=8.2 Hz, 1H), 3.30-3.18 (m, 2H), 1.84 (dq,J=12.8, 8.5 Hz, 1H).

Step C. (S)-1-(4-Chlorobenzyl)-2-oxopyrrolidin-3-yl methanesulfonate

Triethylamine (0.825 mL, 5.92 mmol) and methansulfonyl chloride (0.338mL, 4.34 mmol) was added to a stirred solution of(S)-1-(4-chlorobenzyl)-3-hydroxypyrrolidin-2-one (890 mg, 3.94 mmol) indichloromethane (20 mL) at 0° C.

The reaction mixture was stirred at 0° C. for 1 h. The resulting mixturewas diluted with water and the aqueous mixture was extracted withdichloromethane. The combined organic layers were washed with 10% sodiumbicarbonate solution, dried over sodium sulfate, filtered, andconcentrated in vacuo. The crude material was purified using silica gelcolumn chromatography (0-100% EtOAc). The pure fractions were combinedand concentrated in vacuo to afford(S)-1-(4-chlorobenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (1.1 g,3.62 mmol, 92% yield) as a white solid: LC-MS (M+H)+304.1; ¹H NMR (500MHz, chloroform-d) δ 7.38-7.33 (m, 2H), 7.22-7.17 (m, 2H), 5.25 (dd,J=8.2, 7.6 Hz, 1H), 4.52-4.41 (m, 2H), 3.40-3.31 (m, 4H), 3.25 (dt,J=10.0, 7.3 Hz, 1H), 2.58 (dddd, J=13.7, 8.4, 7.5, 3.3 Hz, 1H),2.33-2.20 (m, 1H).

Step D. (S)-1-(4-Chlorobenzyl)-2-oxopyrrolidin-3-yl methanesulfonate

To a solution of 2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (1.0g, 4.7 mmol, from example 114, step E) in acetonitrile (25 mL) was addeddiisopropylethylamine (2.5 mL, 14 mmol) and it was heated to 60° C. for30 min. To this preheated mixture was then added(S)-1-(4-chlorobenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (1.710 g,5.63 mmol, from step C) in acetonitrile (15 mL). The reaction mixturewas heated at 90° C. for 16 h. The reaction was diluted with sat.aqueous sodium bicarbonate and extracted with EtOAc. The organic layerswere combined and concentrated to a black oil. The oil was purifiedusing silica gel column chromatography (20-100% EtOAc/hexanes then 0-20%MeOH/dichloromethane) to afford1-(4-chlorobenzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(752 mg, 38% yield). Chiral HPLC analysis revealed that the finalproduct was a (3:1) mixture of diastereoisomers, due to partialepimerization. The diastereomeric mixture (750 mg) was separated bypreparative chiral SFC (column=Lux Cellulose-2 (21×250 mm, 5 μm);isocratic solvent=35% methanol in CO₂, 150 bar; temp=35° C.; flowrate=40 mL/min; injection volume=0.75 mL (˜42 mg/mL in MeOH) stackedintervals; λ=220 nM; Peak 1=5.5 min, Peak 2=7.9 min) to afford thetitled compound (482 mg) of Example 116 (the second peak to elute). Datafor Example 116: LC-MS m/z 421 (M+H⁺); ¹H NMR (400 MHz, DMSO-d₆) δ 9.63(s, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.5 Hz, 2H), 7.17-7.03 (m,1H), 6.88 (s, 2H), 4.78-4.46 (m, 1H), 4.38 (d, J=11.5 Hz, 2H), 3.70-3.48(m, 1H), 3.45-3.37 (m, 1H), 3.28-3.03 (m, 2H), 2.82-2.63 (m, 2H),2.61-2.53 (m, 1H), 2.40-2.21 (m, 1H), 2.18-2.02 (m, 1H), 1.98-1.84 (m,1H), 1.82-1.50 (m, 2H).

Example 117 (Peak-1)(S)-1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

and Example 117 (Peak-2)(R)-1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one

A stirred mixture of3-bromo-1-(4-(difluoromethyl)benzyl)pyrrolidin-2-one (100 mg, 0.328mmol, intermediate 2a),2-fluoro-4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (70 mg, 0.328 mmol,from example 114, step E), and triethylamine (0.137 mL, 0.985 mmol) inacetonitrile (2 mL) was heated at 120° C. in a CEM microwave for onehour. The reaction mixture was diluted with water and extracted withethyl acetate (100 mL). The organic layer was washed with brinesolution, dried over sodium sulfate, and evaporated under reducedpressure to give a crude residue. The crude residue was purified viapreparative LC/MS (column: Waters Xbridge C18, 19×150 mm, 5 μm; guardcolumn: Waters XBridge C18, 19×10 mm, 5 μm; mobile phase A: 5:95methanol:water with 10 mM NH₄OAc; mobile Phase B: 95:5 methanol:waterwith 10 mM NH4OAc; Gradient: 15-50% B over 25 min, followed by a 10 minhold at 50% B and 5 min hold at 100% B; flow: 15 ml/min) to afford1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one(68 mg, 46%). The diastereomeric mixture was separated by preparativechiral SFC (column=Chiralpak AD-H (250 mm×21 mm, 5 μm); isocraticsolvent=40% methanol (w/0.25% DEA) in CO₂, 100 bar; temp=25° C.; flowrate=75 g/min; injection volume=1.1 mL (6 mg/mL in MeOH); λ=220 nM; Peak1=3.2 min, Peak 2=5.0 min) to afford the titled compounds of example 117(18 mg of peak-1, and 20 mg of peak-2). Data for example 117, P-1: LC-MSm/z 437 (M+H)+; ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.55 (d, J=8.03 Hz,2H) 7.42 (s, 2H) 6.97-7.04 (m, 1H) 6.62-6.95 (m, 3H) 4.48-4.68 (m, 3H)3.76 (t, J=8.78 Hz, 1H) 3.50 (dt, J=3.31, 1.64 Hz, 0H) 3.25-3.31 (m, 0H)3.11-3.18 (m, 0H) 2.99-3.05 (m, 0H) 2.41-2.71 (m, 3H) 2.16-2.26 (m, 1H)2.08 (dq, J=12.91, 8.79 Hz, 1H) 1.78-1.91 (m, 2H). Data for example 117,P-2: LC-MS m/z 437 (M+H)+; ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.55 (d,J=8.03 Hz, 2H) 7.41 (d, J=8.28 Hz, 2H) 7.00 (dd, J=12.39, 1.91 Hz, 1H)6.62-6.93 (m, 3H) 4.47-4.70 (m, 3H) 3.69-3.77 (m, 1H) 3.38-3.55 (m, 1H)3.24-3.30 (m, 1H) 3.15 (dt, J=3.31, 1.64 Hz, 1H) 2.74-2.83 (m, 2H)2.52-2.72 (m, 2H) 2.44 (td, J=10.02, 4.80 Hz, 1H) 2.03-2.27 (m, 2H)1.76-1.90 (m, 2H).

Biological Methods

Radioligand Binding Assay.

Binding experiments to determine binding to NR2B-subtype NMDA receptorswere performed on forebrains of 8-10 weeks old male Sprague Dawley rats(Harlan, Netherlands) using ³H Ro 25-6981 (Mutel V; Buchy D;Klingelschmidt A; Messer J; Bleuel Z; Kemp J A; Richards J G. Journal ofNeurochemistry, 1998, 70(5):2147-2155. Rats were decapitated withoutanesthesia using a Guillotine (approved by animal ethics committee) andthe harvested brains were snap-frozen and stored at −80° C. for 3-6months for membrane preparation.

For membrane preparation, rat forebrains were thawed on ice for 20minutes in homogenization buffer composed of 50 mM KH₂PO₄ (pH adjustedto 7.4 with KOH), 1 mM EDTA, 0.005% Triton X 100 and protease inhibitorcocktail (Sigma Aldrich). Thawed brains were homogenized using a Douncehomogenizer and centrifuged at 48000×g for 20 min. The pellet wasresuspended in cold buffer and homogenized again using a Douncehomogenizer. Subsequently, the homogenate was aliquoted, snap-frozen andstored at −80° C. for not more than 3-4 months.

To perform the competition binding assay, thawed membrane homogenate wasadded to each well of a 96-well plate (20 μg/well). The experimentalcompounds were serially diluted in 100% DMSO and added to each row ofthe assay plate to achieve desired compound concentrations, keeping theDMSO concentration in the assay plate at 1.33% of the final reactionvolume. Next, ³H Ro 25-6981 (4 nM) was added to the assay plate. Afterincubation for 1 hr at room temperature, the membrane bound radioligandwas harvested on to GF/B filter plates (treated with 0.5% PEI for 1 hrat room temperature). The filter plates were dried at 50° C. for 20mins, incubated with microscint 20 for 10 minutes and finally, thecounts were read on TopCount (Perkin Elmer). Non-specific binding wasdetermined using MK-0657 (the preparation of this compound is describedas example 1 in WO 2004 108705 (40 μM). CPM values were converted to %inhibition and the concentration response curves were plotted usingcustom made software. Each experiment was repeated at least twice toobtain the final binding K₁ values for experimental compounds. Usingthis assay, the compound of example 1 shows a binding Ki of 4 nM.

NR2B Binding Example Structure Ki, nM  1

3  2a

740  2b

1.4  3

1320  4

5000  5

4.4  6a

850  6b

4.7  7

37  8

420  9a

180  9b

1400  9c

5000  9d

160  10

1020  11

510  12

4  13a

41  13b

1.6  14

 15

12  16

560  17

1.6  18a

170  18b

1.5  19

3.9  20

43  21a

37  21b

410  22

2.9  23a

11  23b

1.4  24

4.7  25a

1200  25b

5.3  26

31  27

20  28a

420  28b

10  29

78  30

4.7  31

800  32

100  33a

5000  33b

44  34

670  35

17  36

34  37

21  38

150  39

300  40

480  41a

990  41b

200  42

720  43

150  44, E-1

650  44, E-2

5.7  45, P-1

260  45, P-2

3.1  45, P-3

380  45, P-4

2.5  46, P-1

430  46, P-2

4.3  46, P-3

340  46, P-4

4.0  47, P-1

470  47, P-2

470  47, P-3

3.8  47, P-4

3.4  48, P-1

760  48, P-2

1700  48, P-3

11  48, P-4

13  49, P-1

420  49, P-2

73  50, P-1

5000  50, P-2

890  50, P-3

5000  50, P-4

1300  51, P-1

660  51, P-2

7.6  51, P-3

30  51, P-4

11  52, P-1

690  52, P-2

6.2  52, P-3

89  52, P-4

6.7  53, P-1

1100  53, P-2

5.8  54, P-1

530  54, P-2

8.5  54, P-3

110  54, P-4

26  55, P-1

280  55, P-2

32  55, P-3

130  55, P-4

430  56, P-1

5000  56, P-2

1400  56, P-3

5000  56, P-4

660  57

490  58

8.7  59

81  60

110  61

46  62

6.7  63

10  64

490  65

3.6  66

1500  67

6.5  68

710  69

34  70

180  71

560  72

6.0  73

330  74

680  75

8.0  76

33  77

27  78

190  79

40  80

560  81

3.8  82

860  83

5.0  84

950  85

23  86

78  87

540  88

5.3  89

200  90

77  91, P-1

76  91, P-2

14  92

59  93

67  94

390  95, P-1

54  95, P-2

12  96, P-1

490  96, P-2

18  97

45  98

230  99, P-1

380  99, P-2

22 100

570 101, P-1

13 101, P-2

11 102, P-1

740 102, P-2

30 103

81 104

130 105

180 106, P-1

990 106, P-2

4.6 107, P-1

1200 107, P-2

7.7 108, P-1

1200 108, P-2

15 109

290 110

36 111

590 112, P-1

4.4 112, P-2

8.4 113

33 114, P-1

3.5 114, P-2

180 115

2.7 116

2.0 117, P-1

79 117, P-2

2.9

Ex Vivo Occupancy Assay.

This assay demonstrates that the compound of example 1 occupiesbrain-resident NR2B-subtype receptors in animals after dosing. 7-9 weeksold male CD-1 mice were dosed intravenously in a vehicle consisting of10% dimethylacetamide, 40% PEG-400, 30% hydroxypropyl betacyclodextrin,and 30% water with experimental compounds and the forebrains wereharvested 15 minutes post-dosing by decapitation. The brain samples wereimmediately snap-frozen and stored at −80° C. On the following day, thedosed brain samples were thawed on ice for 15-20 minutes followed byhomogenization using Polytron for 10 seconds in cold homogenizationbuffer composed of 50 mM KH₂PO₄ (pH adjusted to 7.4 with KOH), 1 mMEDTA, 0.005% Triton X 100 and protease inhibitor cocktail (SigmaAldrich). The crude homogenates were further homogenized using a Douncehomogenizer and the homogenized membrane aliquots from all animals wereflash-frozen and stored at −80° C. until further use. The wholehomogenization process was performed on ice.

For determining occupancy, the membrane homogenates were first thawed onice and then needle-homogenized using a 25 gauge needle. The homogenizedmembrane (6.4 mg/ml) was added to a 96-well plate followed by additionof ³H Ro 25-6981 (6 nM). The reaction mixture was incubated for 5minutes on a shaker at 4° C. and then harvested onto GF/B filter plates(treated with 0.5% PEI for 1 hr at room temperature). The filter plateswere dried at 50° C. for 20 mins, incubated with microscint 20 for 10minutes and read on TopCount (Perkin Elmer). Each dose or compound groupconsisted of 4-5 animals. The control group of animals was dosed withvehicle alone. Membrane from each animal was added in triplicates to theassay plate. Non-specific binding was determined using 10 μM Ro 25-6981added to the wells containing membrane homogenates from vehicle-dosedanimals. Specific counts/minute was converted to % occupancy at eachdose of a compound for each animal using the following equation:

${\% \mspace{14mu} {Occupancy}\mspace{14mu} \left( {{animal}\mspace{14mu} A} \right)} = {100 - \left( {\frac{{specific}\mspace{14mu} {CPM}\mspace{14mu} {of}\mspace{14mu} {animal}\mspace{14mu} A}{{Average}\mspace{14mu} {CPM}\mspace{14mu} {from}\mspace{14mu} {control}\mspace{14mu} {group}} \times 100} \right)}$

Using this procedure, the compound of example 46, P-4 shows 95% NR2Breceptor occupancy after a 3 mg/Kg i.v. dose. Drug levels weredetermined by mass spectroscopy in the usual manner. Drug levels in theblood plasma were 1106 nM in at this dose, and drug levels in thehomogonized brain tissue were 1984 nM. The compound of example 114, P-1showed 97% NR2B receptor occupancy after a 3 mg/Kg i.v. dose. Druglevels in the blood plasma were 1800 nM in at this dose, and drug levelsin the homogonized brain tissue were 2200 nM.

hERG Electrophysiology Assay.

The experimental compounds were assessed for hERG activity on HEK 293cells stably expressing hERG channels using patch clamp technique.Coverslips plated with hERG expressing cells were placed in theexperimental chamber and were perfused with a solution composed of (inmM): 140 NaCl, 4 KCl, 1.8 CaCl₂, 1 MgCl₂, 10 Glucose, 10 HEPES (pH 7.4,NaOH) at room temperature. Borosilicate patch pipettes had tipresistances of 2-4 Mohms when filled with an internal solutioncontaining: 130 KCl, 1 MgCl₂, 1 CaCl₂, 10 EGTA, 10 HEPES, 5 ATP-K₂ (pH7.2, KOH). The cells were clamped at −80 mV in whole cell configurationusing an Axopatch 200B (Axon instruments, Union City, Calif.) patchclamp amplifier controlled by pClamp (Axon instruments) software. Uponformation of a gigaseal, the following voltage protocol was repeatedly(0.05 Hz) applied to record tail currents: depolarization step from −80mV to +20 mV for 2 seconds followed by a hyperpolarization step to −65mV (3 seconds) to elicit tail currents and then, back to the holdingpotential. Compounds were applied after stabilization of tail current.First, tail currents were recorded in presence of extracellular solutionalone (control) and subsequently, in extracellular solution containingincreasing compound concentrations. Each compound concentration wasapplied for 2-5 minutes. The percentage inhibition at each concentrationwas calculated as reduction in peak tail current with respect to thepeak tail current recorded in the presence of control solution. Dataanalysis was performed in custom made software. The percent inhibitionsat different concentrations were plotted to obtain a concentrationresponse curve, which was subsequently fitted with a four parameterequation to calculate the hERG IC₅₀ value. Using this procedure, thecompound of example 46, P-4 is a poor inhibitor of the hERG channel,with an IC₅₀=28 μM. The compound of example 114, P-1 is a poor inhibitorof the hERG channel, with an IC₅₀=13.5 μM.

Mouse Forced Swim Test (mFST).

Forced Swim Test (FST) is an animal model used to assess antidepressantcompounds in preclinical studies. The FST was performed similar to themethod of Porsolt et al. with modifications (Porsolt R D, Bertin A,Jalfre M. Behavioral despair in mice: a primary screening test forantidepressants. Arch Int Pharmacodyn Ther 1977; 229:327-36). In thisparadigm, mice are forced to swim in an inescapable cylinder filled withwater. Under these conditions, mice will initially try to escape andeventually develop immobility behavior; this behavior is interpreted asa passive stress-coping strategy or depression-like behavior. Swim tankswere positioned inside a box made of plastic. Each tank was separatedfrom each other by opaque plastic sheets to the height of cylinders.Three mice were subjected to test at a time. Swim sessions wereconducted for 6 min by placing mice in individual glass cylinders (46 cmheight X 20 cm diameter) containing water (20-cm deep, maintained at24-25° C.). At this water level, the mouse tail does not touch thebottom of the container. The mouse was judged to be immobile whenever itremained floating passively without struggling in the water and onlymaking those movements necessary to keep its nose/head above the waterand to keep it afloat. The duration of immobility was evaluated duringthe total 6 min of the test and expressed as duration (sec) ofimmobility. Each mouse was tested only once. At the end of each session,mice were dried with a dry cloth and returned to their home cage placedon a thermal blanket to prevent hypothermia. Water was replaced aftereach trial. All testing sessions were recorded with a video camera (SonyHandicam, Model: DCR-HC38E; PAL) and scoring was done using the ForcedSwim Scan, Version 2.0 software (Clever Systems Inc., Reston, Va., USA;see Hayashi E, Shimamura M, Kuratani K, Kinoshita M, Hara H. Automatedexperimental system capturing three behavioral components during murineforced swim test. Life Sci. 2011 Feb. 28; 88(9-10):411-7 and Yuan P,Tragon T, Xia M, Leclair C A, Skoumbourdis A P, Zheng W, Thomas C J,Huang R, Austin C P, Chen G, Guitart X. Phosphodiesterase 4 inhibitorsenhance sexual pleasure-seeking activity in rodents. Pharmacol BiochemBehav. 2011; 98(3):349-55). For NCE testing: Test compound wasadministered in mice 15 min before swim session by i.v. route andimmobility time was recorded for next 6 min. At the end of FST, themouse were euthanized by rapid decapitation method and plasma and brainsamples were collected and stored under −80° C. till further analysis.In the mouse forced swim assay, the compound of example 1 was dosedintravenously in a vehicle of 30% hydroxypropyl betacyclodextrin/70%citrate buffer pH 4 at a 5 mL/Kg dosing volume. The compound of example46, P-4 demonstrated a statistically significant decrease in immobilitytime at 1 mg/Kg under these conditions. Drug levels were 268+/−128 nM inthe plasma and 749+/−215 nM in the brain at this dose. The NR2B receptoroccupancy was determined as reported above and was determined to be 73%.The compound of example 224, P-2 demonstrated a statisticallysignificant decrease in immobility time at 1 mg/Kg under these sameconditions. Drug levels were 360 nM in the plasma. The NR2B receptoroccupancy was determined to be 79%.

We claim:
 1. A pharmaceutical composition comprising the compound (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 